Dopamine d3 receptor antagonist compounds

ABSTRACT

The disclosure is directed to novel dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, including treating drug dependency and psychosis.

RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No. 15/975,466filed May 9, 2018, allowed, which is a continuation of U.S. applicationSer. No. 15/522,863 filed Apr. 28, 2017, issued as U.S. Pat. No.10,000,477, which is a § 371 national stage of PCT Application No.PCT/GB2015/053272 filed Oct. 30, 2015, which claims priority to UnitedKingdom Application Numbers GB1419430.2 and GB1419433.6 both filed Oct.31, 2014, the disclosures of which are incorporated by reference hereinin their entirety FIELD OF THE INVENTION

The present invention relates to novel compounds, processes for theirpreparation, intermediates used in these processes, pharmaceuticalcompositions containing them and their use in therapy, as modulators ofdopamine D₃ receptors.

BACKGROUND OF THE INVENTION

Dopamine is a neurotransmitter that plays an essential role in normalbrain functions. As a chemical messenger, dopamine is similar toadrenaline. In the brain, dopamine is synthesized in the pre-synapticneurons and released into the space between the pre-synaptic andpost-synaptic neurons. Dopamine affects brain processes that controlmovement, emotional response, and ability to experience pleasure andpain. Therefore, the regulation of dopamine plays an important role inmental and physical health. Neurons containing dopamine are clustered inthe midbrain area called the substantia nigra. Abnormal dopaminesignaling in the brain has been implicated in a substantial number ofpathological conditions, including drug abuse, depression, anxiety,schizophrenia, Tourette's syndrome, eating disorders, alcoholism,chronic pain, obsessive compulsive disorders, restless leg syndrome, andParkinson's Disease.

Dopamine molecules bind to and activate dopamine receptors on thepost-synaptic neurons. Dopamine molecules then are transported throughthe dopamine transporter protein (DAT) back into the pre-synapticneurons, where they are metabolized by monoamine oxidase (MAO). Inconditions such as drug abuse, the drug binds to the dopaminetransporter and blocks the normal flow of dopamine molecules. Excessconcentrations of dopamine cause over-activation of dopamine receptors.In other conditions, such as Parkinson's Disease, lack of sufficientdopamine receptors in the brain causes insufficient activation ofdopamine receptors.

Dopaminergic neurotransmission is mediated by five dopamine receptors,which can be grouped into the D1-like (i.e., D1 and D5) and D2-like(i.e., D2, D3, and D4) receptor subtypes. The dopamine D3 receptor hasbeen implicated as an important target for agents currently usedclinically for the treatment of schizophrenia, Parkinson's disease,depression, and other neurological diseases. Studies have also providedevidence that potent and selective D3 receptor antagonists may have atherapeutic potential as pharmacotherapies for the treatment of drugabuse. Therefore, considerable effort has been devoted to the discoveryand development of potent and selective D3 receptor antagonists.

SUMMARY OF THE INVENTION

A new class of compounds which have affinity for dopamine receptors, inparticular the dopamine D₃ receptor has been found. These compounds areuseful in the treatment of conditions wherein modulation, especiallyantagonism/inhibition, of the D₃ receptor is beneficial, e.g. to treatdrug dependency or as antipsychotic agents.

The disclosure provides compounds of formula (I) or pharmaceuticallyacceptable salts thereof: The disclosure provides methods ofantagonizing the D3 receptor to treat diseases, including psychosis andsubstance abuse.

DETAILED DESCRIPTION

The present invention provides a compound of formula (I) or apharmaceutical acceptable salt thereof:

wherein

A is a saturated 3-6 membered carbocyclic ring and such ring may besubstituted by one or more C₁₋₄alkyl group;

B is a saturated 4-6 membered heterocyclic ring, in which one or twocarbon atoms may be replaced by an heteroatom selected from at least oneNitrogen or an Oxygen and the linking atom is always a Nitrogen atom;such ring may be also substituted at the carbon atoms or, possibly, at adifferent Nitrogen atom, by one or more C₁₋₄alkyl group;

G is aryl or a 5-6 membered heteroaromatic group or 8-11 memberedheteroaromatic group, which may be benzofused or optionally substitutedby 1, 2, 3 4 or 5 substituents selected from the group consisting of:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄ alkyl, haloC₁₋₄alkoxy, SF₅, C(═O)NH₂ and C(═O)(O)_(z)R₃;

W is S, SO₂, O, CHR₂ or NR₃;

n is 0 or 1;

m is 1 or 2;

p is 1 or 2;

z is each independently 0 or 1;

R is hydrogen or C₁₋₄alkyl; C₁₋₄alkoxy;

R₁ is each independently hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₂ is each independently hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₃ is each independently hydrogen or C₁₋₄alkyl;

R₄ is each independently hydrogen or C₁₋₄alkyl; or —C(═O)C₁₋₄alkyl;—C(═O)C₁₋₄alkoxyC₁₋₄alkyl; —C(═O)C₃₋₆cycloalkyl;

R₅ is each independently hydrogen or C₁₋₄alkyl;

R₆ is each independently hydrogen or C₁₋₄alkyl;

R₇ is each independently halogen, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

G₁ is a phenyl or a 5-6-membered heteroaromatic group or a 8-11 memberedheteroaromatic group; any of which groups may be optionally substitutedby 1, 2, 3 or 4 substituents selected from the group consisting of:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy, SF₅, C(═O)NH₂ andC(═O)(O)_(z)R₃;

Y is phenyl or a moiety selected from the group consisting of: 5-6membered heteroaromatic group, a 8-11 membered heteroaromatic group, asaturated mono 3-7 membered carbocyclic group and a 8-11 memberedbicyclic carbocyclic group, and for any of such groups one or more ringcarbons may be replaced by N(R₄)_(z), O, S; any of which groups may beoptionally substituted by 1, 2 or 3 substituents selected from: halogen,cyano, hydroxyl, C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, oxo, —NHC(═O)C₁₋₄alkyl, —NR₅R₆, SF₅,—(CH₂)_(z)C(═O)NR₅R₆, —C(═O)(O)_(z)R₃, —C₁₋₄alkylCN, —SO₂NR₅R₆, Y′ orOY′;

Y′ is phenyl, or a 5-6-membered heteroaromatic group optionallysubstituted by 1 or 2 R₇ groups; provided that Y, Y′ and G₁ are notsimultaneously phenyl.

The term “aryl” refers to an aromatic carbocyclic moiety such as phenyl,biphenyl or naphtyl.

The term “5-6-membered heteroaromatic group” refers to a monocyclic 5-or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4heteroatoms, for example from 1 to 3 heteroatoms, selected from O, N andS. When the group contains 2-4 heteroatoms, one may be selected from O,N and S and the remaining heteroatoms may be N. Examples of 5 and6-membered heteroaromatic groups include pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,furyl, thienyl, thiadiazolyl, pyridyl, triazolyl, triazinyl,pyridazinyl, pyrimidinyl and pyrazinyl.

The term “8-11-membered heteroaromatic group” refers to a bicyclicaromatic ring system containing a total of 8, 9, 10 or 11 ring atoms,wherein 1, 2, 3 or 4 or 5 of the ring atoms are a heteroatomindependently selected from O, S and N. The term includes bicyclicsystems wherein both rings are aromatic, as well as bicyclic ringsystems wherein one of the rings is partially or fully saturated and theother ring is aromatic. Examples of 8- to 11-membered bicyclicheteroaromatic groups having 1, 2, 3, 4 or 5 heteroatoms, in which bothrings are aromatic, include: 6H-thieno[2,3-b]pyrrolyl,imidazo[2,1-b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl,[1,3]thiazolo[3,2-b][1,2,4]triazolyl, indolyl, isoindolyl, indazolyl,benzimidazolyl e.g. benzimidazol-2-yl, benzoxazolyl e.g.benzoxazol-2-yl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzothienyl, benzofuranyl, naphthridinyl, quinolyl, quinoxalinyl,quinazolinyl, cinnolinyl, isoquinolyl, 1H-imidazo[4,5-b]pyridin-5-yl and[1,2,4]triazolo[4,3-a]pyridinyl. Examples of 8- to 11-membered bicyclicheteroaromatic groups having 1, 2, 3, 4 or 5 heteroatoms, in which oneof the rings is partially or fully saturated includedihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl,tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl andbenzoazepinyl.

The term “C₁₋₄alkyl” refers to an alkyl group having from one to fourcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term“n-C₁₋₄alkyl” refers to the unbranched alkyls as defined above.

The term “C₁₋₄alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to four carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxyand tert-butoxy.

The term —C₁₋₄alkylCN refers to an C₁₋₄alkyl group substituted by acyano group, for example —CH₂CN.

The term “—C(═O)C₁₋₄alkoxyC₁₋₄alkyl” refers to the carbon of theC₁₋₄alkoxy being linked to the C(═O) group, to give, for example, agroup of the formula —C(O)—(CH₂)₁₋₄—O—C₁₋₄alkyl

The term “halogen” and its abbreviation “halo” refer to fluorine (F),chlorine (Cl), bromine (Br) or iodine (I). Where the term “halo” is usedbefore another group, it indicates that the group is substituted by one,two or three halogen atoms. For example, “haloC₁₋₄alkyl” refers togroups such as trifluoromethyl, bromoethyl, trifluoropropyl, and othergroups derived from C₁₋₄alkyl groups as defined above; and the term“haloC₁₋₄alkoxy” refers to groups such as trifluoromethoxy, bromoethoxy,trifluoropropoxy, and other groups derived from C₁₋₄alkoxy groups asdefined above.

The term “saturated mono 3-7 membered carbocyclic group” and the term“8-11 membered bicyclic carbocyclic group” refers to 3 or 4, 5, 6, or7-membered saturated monocyclic group or 8, 9, 10, 11 membered saturatedbicyclic wherein 1, 2, 3, 4 or 5 of the carbon atoms are optionallyreplaced by a heteroatom independently selected from O, S and N(R₄)_(z)(for example NR₃) and which is partially or fully saturated. Examples of3-7 membered carbocyclic group containing heteroatoms which are fullysaturated include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,isothiazolyl, thiazolyl, tetrahydrofuranyl, dioxolanyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, dioxanyl,tetrahydro-2H-pyranyl and dithianyl.

Examples of a saturated 3-7 membered (for example 3-6 membered)carbocyclic groups or rings containing only carbon atoms in the ringwhich are fully saturated include C₃₋₇cycloalkyl, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Examples of carbocyclic groups containing only carbon atoms in the ringwhich are partially saturated include C₄₋₇cycloalkenyl, for examplecyclopentenyl and cyclohexenyl.

Examples of “3-7 membered carbocyclic group containing heteroatoms”which are partially saturated 5 or 6-membered monocyclic rings includeoxazolinyl, isoaxazolinyl, imidazolinyl, pyrazolinyl,1,2,3,6-tetrahydropyridyl and 3,6-dihydro-2H-pyranyl.

Examples of “8-11 membered bicyclic carbocyclic group” includedecahydroquinolinyl, octahydro-2H-1,4-benzoxazinyl,8-oxabicyclo[3.2.1]octan-3-yl, 8-oxa-3-azabicyclo[3.2.1]octane andoctahydro-1H-cyclopenta[b]pyridinyl.

Examples of partially saturated “8-11 membered bicyclic groups” include2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl and2,3,4,5-tetrahydro-1H-3-benzazepinyl.

As will be recognised B is a saturated 4-6 membered heterocyclic ringwhich contains at least 1 ring nitrogen and wherein B is linked to the—(CHR)_(n)(CR₁R₂)_(p)— by the ring nitrogen group in B. In addition tothat ring nitrogen B optionally contains one or two further ring heteroatoms selected from O and N. B is unsubsituted or may be substituted aton a ring carbon or an available ring nitrogen atom by one or moreC₁₋₄alkyl group.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts.Physiologically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent compounds. Such salts must clearly have a physiologicallyacceptable anion or cation. Suitably physiologically acceptable salts ofthe compounds of the present invention include acid addition saltsformed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, andwith organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic,maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic,isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic,anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic,alginic, galacturonic and arylsulfonic, for example benzenesulfonic andp-toluenesulfonic, acids; base addition salts formed with alkali metalsand alkaline earth metals and organic bases such asN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; andinternally formed salts. Salts having a non-physiologically acceptableanion or cation are within the scope of the invention as usefulintermediates for the preparation of physiologically acceptable saltsand/or for use in non-therapeutic, for example, in vitro, situations.

In a preferred embodiment compounds of formula (IA) are provided inwhich A and B of compounds of formula (I) may be selected from thefollowing:

and wherein G, G₁, W, Y, n, m, p, z, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula (II)are provided in which A and B of compound of formula (I) correspond to a5-azaspiro[2.4]heptane derivative

wherein G, G₁, W, Y, n, m, p, z, R₁, R₂, and R₃ are defined as above forcompounds of formula (I).

In another embodiment of the present invention compounds of formula(III) are provided in which A and B of compound of formula (I)correspond to a 6-azaspiro[3.4]octane derivative

wherein G, G₁, W, Y, n, m, p, z, R₁, R₂, and R₃ are defined as above forcompounds of formula (I).

In another embodiment of the present invention compounds of formula (IV)are provided in which A and B of compound of formula (I) correspond to a6-azaspiro[2.5]octane derivative

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula (V)are provided in which A and B of compound of formula (I) correspond to a5-azaspiro[2.5]octane derivative

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

The position of the substituent G with respect to the ring B may be in a“cis” or “trans” disposition or not.

Relative stereochemistry “cis” is represented by using the boldhighlight of the bonds, while the “trans” relative stereochemistry isrepresented by using bold and dotted highlight of the bonds.

In a preferred embodiment compounds of formula (IB) are provided inwhich A and B of compounds of formula (I) may be selected from thefollowing:

and wherein G, Gi, W, Y, n, m, p, z, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula(IIA) are provided which correspond to the compounds of formula (II)having “cis” disposition, represented by the bold highlight of the bonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula(IIB) are provided which correspond to the compounds of formula (II)having “trans” disposition, represented by the bold and dotted highlightof the bonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula(IIIA) are provided which correspond to the compounds of formula (III)having “cis” disposition, represented by the bold highlight of the bonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula(IIIB) are provided which correspond to the compounds of formula (III)having “trans” disposition, represented by the bold and dotted highlightof the bonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula (VA)are provided which correspond to the compounds of formula (V) having“cis” disposition, represented by the bold highlight of the bonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

In another embodiment of the present invention compounds of formula (VB)are provided which correspond to the compounds of formula (V) having“trans” disposition, represented by the bold and dotted highlight of thebonds

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

It will be appreciated that compounds of formula (IIA) possess at leasttwo chiral centres, namely at position 1 and 3 in the5-azaspiro[2.4]heptane portion of the molecule. Because of the fixed cisdisposition, the compounds may exist in two stereoisomers which areenantiomers with respect to the chiral centres in the cyclopropane. Itwill also be appreciated, in common with most biologically activemolecules that the level of biological activity may vary between theindividual stereoisomers of a given molecule.

In compounds of formula (IIA) there are at least two chiral centres,which are located in the cyclopropane portion, as depicted below (thebold highlight of the bonds means the “cis” configuration):

Depending on the substituents on the G group, the configuration maybecome (1S, 3S) due to different Cahn-Ingold-Prelog nomenclaturepriorities.

In a further embodiment of the present invention compounds of formula(IIC) are provided that correspond to stereochemical isomers ofcompounds of formula (IIA), enriched in configuration (1R,3S) or (1S,3S)

wherein G, G₁, W, Y, n, m, p, z, R, R₁, R₂, and R₃ are defined as abovefor compounds of formula (I).

It is intended in the context of the present invention thatstereochemical isomers enriched in configuration (1R,3S) or (1S,3S) offormula (IIC) correspond in one embodiment to at least 90% enantiomericexcess (e.e). In another embodiment the isomers correspond to at least95% e.e. In another embodiment the isomers correspond to at least 99%e.e.

The strategy for determining the absolute configuration of the compoundsof the present invention comprised as a first step the preparation ofthe chiral intermediate,(1R,3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,

by preparation of(1R,3S/1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(preparation 14) and resolution of the racemic mixture by use of chiralHPLC procedure (preparation 15).

The assignment of the absolute configuration of the title compound wasdetermined by a single crystal X-ray structure obtained from a crystalof 5-(4-methylbenzenesulfonyl)-(1R,3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane derived from thedesired enantiomer and crystallized in EtOH as solvent (see preparation290) to obtain a single crystal.

The present molecule exhibits two stereocenters. According to theabsolute structure determination, the configuration at the carbon atomcorresponding to Cl is R, whereas the configuration at the carbon atomcorresponding to C3 is S.

In order to further confirmed the absolute stereochemistry also theopposite enantiomer (1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane was analogouslyderivatized (see preparation 291) and submitted to the same analysesthat confirmed that the configuration at the carbon atom correspondingto Cl is S, whereas the configuration at the carbon atom correspondingto C3 is R.

For those compounds synthesised from(1R,3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane or(1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (with knownabsolute stereochemistry based on X-ray structure) a common trend wasrecognised between absolute configuration of the 5-azaspiro[2.4]heptanemoiety and measured binding activity at the dopamine D3 receptor foreach pair of enantiomers. For the remainder of the compounds of thepresent invention, where stereoisomers were evaluated separately,absolute configuration was assigned based on a reasonable assumption bya skilled person in the art, i.e. absolute configuration was thenassigned based on measured binding activity at the dopamine D3 receptorfor both enantiomers and comparison with the data of those compoundswhich were subjected to detailed analysis.

Also provided are compounds of the formula (PI), or a pharmaceuticallyacceptable salt thereof:

wherein:

A is a saturated 3-6 carbocyclic ring and such ring may be substitutedby one or more C₁-4alkyl group;

B is a saturated 4-6 carbocyclic ring, in which one or two carbon atomsmay be replaced by an heteroatom selected from at least one Nitrogen oran Oxygen and the linking atom is always a Nitrogen atom; such ring maybe also substituted at the carbon atoms or, possibly, at the differentNitrogen atom, by one or more C₁₋₄alkyl group;

G is aryl or a 5-6 membered heteroaromatic group or 8-11 memberedheteroaromatic group, which may be benzofused or optionally substitutedby 1, 2, 3 or 4 substituents selected from the group consisting of:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁-4alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃;

W is S, SO₂, O, CHR₂, NR₃;

n is 0 or 1;

m is 1 or 2;

p is 1 or 2;

R is hydrogen or C₁₋₄alkyl; C₁₋₄alkoxy;

R₁ is hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₂ is hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₃ is hydrogen or C₁₋₄alkyl;

G₁ is a phenyl group or a 5-6-membered heteroaromatic group or a 8-11membered heteroaromatic group, any of which groups may be optionallysubstituted by 1, 2, 3 or 4 substituents selected from the groupconsisting of: halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂,C(═O)OR₃;

Y is H or a moiety selected from the group consisting of: 5-6 memberedheteroaromatic group, saturated mono 3-7 membered carbocyclic group or8-11 membered bicyclic carbocyclic group in which one or more atomcarbons may be replaced by NR₃, O, S; any of which groups may beoptionally substituted by one or two substituents selected from:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃; or,when G₁ is a phenyl group, G₁ and Y may be fused together to form abenzofused aromatic or heteroaromatic system which might be optionallysubstituted by one or two substituents selected from: halogen, cyano,hydroxy, amide, ester, amino C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅.

In another embodiment compounds of formula (PII) are provided in which Aand B of compound of formula (PI) correspond to a 5-azaspiro[2.4]heptanederivative

In another embodiment compounds of formula (PIII) are provided in whichA and B of compound of formula (PI) correspond to a6-azaspiro[3.4]octane derivative

In another embodiment compounds of formula (PIV) are provided in which Aand B of compound of formula (PI) correspond to a 6-azaspiro[2.5]octanederivative

The position of the substituent G with respect to the ring B may be in a“cis” or “trans” disposition or not.

Relative stereochemistry “cis” is represented by using the boldhighlight of the bonds, while the “trans” relative stereochemistry isrepresented by using bold and dotted highlight of the bonds.

In another embodiment compounds of formula (PIIA) are provided whichcorrespond to the compounds of formula (PII) having “cis” disposition,represented by the bold highlight of the bonds

wherein G, G₁, W, Y, n, m, p, R₁, R₂, and R₃ are defined as above forcompounds of formula (PI).

In another embodiment compounds of formula (PIIB) are provided whichcorrespond to the compounds of formula (PII) having “trans” disposition,represented by the bold highlight of the bonds

wherein G, p, R₁, R₂, R₃, R₄, and R₅ are defined as above for compoundsof formula (PI).

In another embodiment compounds of formula (PIIIA) are provided whichcorrespond to the compounds of formula (PIII) having “cis” disposition,represented by the bold highlight of the bonds

wherein G, G₁, W, Y, n, m, p, R₁, R₂, and R₃ are defined as above forcompounds of formula (PI).

In another embodiment compounds of formula (PIIIB) are provided whichcorrespond to the compounds of formula (PIII) having “trans”disposition, represented by the bold highlight of the bonds

wherein G, p, R₁, R₂, R₃, R₄, and R₅ are defined as above for compoundsof formula (PI).

Also provided are compounds of the formula (PNI), or a pharmaceuticallyacceptable salt thereof:

wherein

A and B are selected from:

G is phenyl or a 5-6 membered heteroaromatic group or 8-11 memberedheteroaromatic group, which may be benzofused or optionally substitutedby 1, 2, 3 or 4 substituents selected from the group consisting of:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃;

W is S, SO₂, O, CHR₂, NR₃;

n is 0 or 1;

m is 1 or 2;

p is 1 or 2;

R is hydrogen or C₁₋₄alkyl; C₁₋₄alkoxy;

R₁ is hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₂ is hydrogen or F, C₁₋₄alkyl; OH, C₁₋₄alkoxy;

R₃ is hydrogen or C₁₋₄alkyl;

G₁ is a phenyl group or a 5-6-membered heteroaromatic group or a 8-11membered heteroaromatic group, any of which groups may be optionallysubstituted by 1, 2, 3 or 4 substituents selected from the groupconsisting of: halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂,C(═O)OR₃;

Y is H or a moiety selected from the group consisting of: 5-6 memberedheteroaromatic group, saturated mono 3-7 membered carbocyclic group or8-11 membered bicyclic carbocyclic group in which one or more atomcarbons may be replaced by NR₃, O, S; any of which groups may beoptionally substituted by one or two substituents selected from:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃; or,when G₁ is a phenyl group, G₁ and Y may be fused together to form abenzofused aromatic or heteroaromatic system which might be optionallysubstituted by one or two substituents selected from: halogen, cyano,hydroxy, amide, ester, amino C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, SF₅.

Suitably in the compounds of the formulae (PI) to (PIV), (PIIA), (PIIB),(PIIIA), (PIIIB) and (PN1) Y is not H.

Suitably in the compounds of the formulae (PI) to (PIV), (PIIA), (PIIB),(PIIIA), (PIIIB) and (PN1) the group —(CR₁R₂)_(p)—W-G₁-is present in thecompound.

Particular compounds of the invention include, for example, compounds ofthe formulae (I), (IA), (IB), (II), (IIA), (IIB), (III), (IIIA), (IIIB),(IV), (V), (VA) or (VB), or pharmaceutically acceptable salts andpro-drugs thereof, wherein, unless otherwise stated, each of A, B, G,G¹, Y, Y′, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, n, m, p and z has any of themeanings defined hereinbefore or in any of paragraphs (1) to (42)hereinafter:—

(1) A in formula (I) is a saturated 3-6 membered carbocyclic ring andsuch ring may be substituted by one or more C₁₋₄alkyl group, wherein thecarbocyclic ring contains only carbon atoms in the ring.

(2) A in formula (I) is selected from

(3) G is is aryl or a 5-6 membered heteroaromatic group or 8-11 memberedheteroaromatic group, which may be benzofused or optionally substitutedby 1, 2, 3 or 4 substituents selected from the group consisting of:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃.

(4) G is phenyl or pyridyl optionally substituted by 1, 2, 3, 4 or 5(for example 1 or 2) substituents independently selected from the groupconsisting of: halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino,C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy, —C(═O)NH₂ and—C(═O)(O)_(z)R₃.

(5) G is phenyl or pyridyl optionally substituted by 1, 2, 3, 4 or 5(for example 1 or 2) substituents independently selected from the groupconsisting of: halogen, cyano, hydroxyl, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy and C₁₋₄alkoxy.

(6) G is phenyl or pyridyl, optionally substituted by 1, 2 or 3 groupsindependently selected from halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

(7) G is phenyl or pyridyl, optionally substituted by 1 or 2 groupsindependently selected from fluoro, chloro and trifluoromethyl.

(8) G is phenyl optionally substituted by 1, 2, 3, 4 or 5 (for example 1or 2) substituents independently selected from the group consisting of:halogen, cyano, hydroxyl, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy andC₁₋₄alkoxy.

(9) G is phenyl, optionally substituted by 1, 2 or 3 groupsindependently selected from halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

(10) G is phenyl optionally substituted by 1 or 2 groups independentlyselected from fluoro, chloro and trifluoromethyl.

(11) G is phenyl.

(12) G is phenyl substituted by 1, 2 or 3 (for example 1 or 2) groupsindependently selected from halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

(13) G is pyridyl optionally substituted by haloC₁₋₄alkyl, for exampletrifluoromethyl. For example G is 6-(trifluoromethyl)pyridin-3-yl. Forexample G is pyridyl.

(14) G is 4-(haloC₁₋₄alkyl)phenyl, for example 4-trifluoromethylphenyl.

(15) G is phenyl, 4-trifluoromethyl-phenyl,2-fluoro-4-trifluoromethyl-phenyl, 2,4-difluorophenyl, 4-fluorophenyl,2-trifluoromethyl-phenyl, 2-trifluoromethyl-4-fluorophenyl or3,5-dichlorophenyl.

(16) The group (CHR)_(n)(CR₁R₂)_(m)(CR₁R₂)_(p) is selected from

(17) The group (CHR)_(n)(CR₁R₂)_(m)(CR₁R₂)_(p) is

(18) W is selected from S, O and CHR₂.

(19) W is CHR₂.

(20) W is S or O.

(21) W is S.

(22) The group —(CHR)_(n)(CR₁R₂)_(m)(CR₁R₂)_(p)W— is

(23) W is S and R, R₁ and R₂ are hydrogen.

(24) G₁ is is a phenyl group or a 5-6-membered heteroaromatic group or a8-11 membered heteroaromatic group, any of which groups may beoptionally substituted by 1, 2, 3 or 4 substituents selected from thegroup consisting of: halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂,C(═O)OR₃.

(25) G₁ is phenyl or a 5-6-membered heteroaromatic group any of whichgroups may be optionally substituted by 1, 2, 3 or 4 substituentsindependently selected from the group consisting of: halogen, cyano,hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, C₁-4alkoxy, SF₅, —C(═O)NH₂ and —C(═O)(O)_(z)R₃.

(26) G₁ is a phenyl or a 5-6-membered heteroaromatic group any of whichgroups may be optionally substituted by 1 or 2 substituents selectedfrom the group consisting of: halogen, hydroxyl, C₁₋₄alkyl,haloC₁₋₄alkyl, haloC₁₋₄alkoxy and C₁₋₄alkoxy.

(27) G₁ is a 5-6-membered heteroaromatic group optionally substituted by1, 2, 3 or 4 (for example 1, 2, or 3) substituents independentlyselected from the group consisting of: halogen, cyano, hydroxyl, amino,C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy,—C(═O)NH₂ and —C(═O)(O)_(z)R₃.

(28) G₁ is a 5-6-membered heteroaromatic group containing at least onering nitrogen and optionally one or two additional ring hetero atomsselected from O and S, wherein the heteroaromatic group is optionallysubstituted by 1, 2, 3 or 4 (for example 1, 2, or 3) substituentsindependently selected from the group consisting of: halogen, cyano,hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, C₁₋₄alkoxy, —C(═O)NH₂ and —C(═O)(O)_(z)R₃.

(29) G₁ is a 5-6-membered heteroaromatic group containing at least onering nitrogen (for example 1, 2 or 3 ring nitrogens) wherein theheteroaromatic group is optionally substituted by 1, 2, 3 or 4 (forexample 1, 2, or 3, preferably 1 or 2) substituents independentlyselected from the group consisting of: halogen, cyano, hydroxyl, amino,C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄ alkoxy, C₁₋₄alkoxy,—C(═O)NH₂ and —C(═O)(O)_(z)R₃.

(30) G₁ is a 5-6-membered heteroaromatic group any of which groups maybe optionally substituted by 1 or 2 substituents selected from the groupconsisting of: C₁₋₄alkyl and haloC₁₋₄alkyl.

(31) G₁ is a 5-membered heteroaromatic group containing at least onering nitrogen (for example 1, 2 or 3 ring nitrogens) wherein theheteroaromatic group is optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of: halogen, cyano,hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy and C₁₋₄alkoxy; optionally wherein the heteroaromaticgroup is optionally substituted by 1 or 2 substituents selected from thegroup consisting of: C₁₋₄alkyl and haloC₁₋₄alkyl.

(32) G₁ is any of the groups set out in paragraphs (24) to (31), whereinG₁ is linked to W and Y by carbon atoms in the G₁ ring.

(33) G₁ is a triazole, for example 1,2,4-triazole optionally substitutedby C₁₋₄alkyl.

(34) G₁ is

wherein R_(a) is H or C₁₋₄alkyl. Suitably R_(a) is C₁₋₄alkyl.

(35) G₁ is

(36) Y is a moiety selected from the group consisting of: 5-6 memberedheteroaromatic group, saturated mono 3-7 membered carbocyclic group or8-11 membered bicyclic carbocyclic group in which one or more atomcarbons may be replaced by NR₃, O, S; any of which groups may beoptionally substituted by one or two substituents selected from:halogen, cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅, C(═O)NH₂, C(═O)OR₃.

(37) Y is selected from phenyl, a 5-6-membered heteroaromatic group,C₃₋₇cycloalkyl,

any of which groups may be optionally substituted by 1, 2 or 3substituents selected from: halogen, cyano, hydroxyl, C₁₋₄alkylamino,C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, oxo,—NHC(═O)C₁₋₄alkyl, —NR₅R₆, SF₅, —(CH₂)_(z)C(═O)NR₅R₆, —C(═O)(O)_(z)R₃,CH₂CN, SO₂NH₂, Y′ or OY′; and wherein a ring NH in Y is optionallysubstituted by R₄; and

Y′ is phenyl, or a 5-6-membered heteroaromatic group optionallysubstituted by 1 or 2 R₇ groups; provided that Y, Y′ and G₁ are notsimultaneously phenyl.

(38) Y is selected from phenyl, oxazolyl, isoxazolyl, furanyl,thiazolyl, isothiazolyl, pyrrolyl, imadazolyl, thiophenyl, thiodiazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,2-dihydropyridinyl,oxanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, cyclopropyl, cyclobutyl,cyclohexyl,

any of which groups may be optionally substituted on a ring carbon atomby 1, 2 or 3 substituents selected from: halogen, cyano, hydroxyl,C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,oxo, —NHC(═O)C₁₋₄alkyl, —NR₅R₆, —(CH₂)_(z)C(═O)NR₅R₆, —C(═O)R₃, CH₂CN,SO₂NH₂, Y′ or OY′; and wherein a ring NH in Y is optionally substitutedby R₄; and

Y′ is phenyl, oxadiazolyl, tetrazolyl, pyrazolyl, triazolyl, oxazolyl orpyridyl, optionally substituted by 1 or 2 R₇ groups; provided that Y, Y′and G₁ are not simultaneously phenyl.

(39) Y is phenyl substituted by 1 or 2 substituents (for example 1substituent) selected from cyano, CH₂CN, —C(═O)R₃, —(CH₂)_(z)C(═O)NR₅R₆,—SO₂NH₂ and Y′, wherein Y′ is selected from oxadiazolyl, tetrazolyl,triazolyl and oxazolyl, which Y′ is optionally substituted by C₁₋₄alkyl.For example Y is phenyl substituted by 1 substituent selected fromcyano, CH₂CN, acetyl, —CH₂C(═O)NH₂, —C(═O)NH₂, —SO₂NH₂ and Y′, whereinY′ is selected from oxadiazolyl, tetrazolyl, triazolyl and oxazolyl,which Y′ is optionally substituted by methyl.

(40) Y is selected from pyridyl, pyrimidinyl, pyrazinyl any of whichgroups may be optionally substituted by 1 or 2 substituents selectedfrom: fluoro, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, and—C(═O)NR₅R₆. For example Y is pyridyl optionally substituted by 1 or 2substituents selected from: C₁₋₄alkyl and —C(═O)NH₂.

(41) Y is selected from the group consisting of:

(i) phenyl optionally substituted by one or two substituents selectedfrom: cyano, C(═O)NH₂, sulphonamide, acetyl, CH₂CN, CH₂C(═O)NH₂ or Y′.Preferably Y′ is a 5-membered heteroaromatic group (e.g. Y is selectedfrom 4-(1H-1,2,3,4-tetrazol-5-yl)phenyl, 4-(1,3,4-oxadiazol-2-yl)phenyl,4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl,4-(4H-1,2,4-triazol-4-yl)phenyl, 4-(1,3-oxazol-2-yl)phenyl, and3-(1,3-oxazol-2-yl)phenyl);

(ii) a saturated mono 3-7 membered carbocyclic group in which 0 or 1 or2 carbon atoms are replaced by a heteroatom independently selected fromO or NR₃ (e.g. cyclohexyl, morpholinyl, piperidinyl, tetrahydropyranyl,azetidinyl or piperidin-2-one) optionally substituted by one or moresubstituents selected from —NHC(═O)C₁₋₄alkyl, —NR₅R₆, C₁₋₄alkyl; in amore preferred embodiment R₃ is C(═O)C₁₋₄alkyl;

(iii) a 8-11 membered bicyclic carbocyclic group (e.g.3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}), optionally substitutedby one or more (for example 1 or 2) C₁₋₄alkyl;

(iv) a 5-6 membered heteroaromatic group (e.g. oxazolyl, thiazolyl,1-methyl-1H-pyrazol-4-yl, furanyl, thiophenyl, 1-methyl-1H-pyrrolyl,thiadiazolyl, piridinyl, 1,2-dihydropyridin-2-one, pirimidinyl, pirazyl,piridazinyl) optionally substituted by one or two substituents selectedfrom: halogen, cyano, hydroxyl, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,(CH₂)_(z)C(═O)N(R₄R₅), Y′ and OY′. In a more preferred embodimentC₁₋₄alkyl is methyl, haloC₁₋₄alkyl is trifluoromethyl, C₁₋₄alkoxy ismethoxy and Y′ is phenyl or pyridine;

(v) a 8-11 membered heteroaromatic group in which 1 or 2 or 3 atomcarbons may be replaced by N, optionally substituted by one or more (forexample 1 or 2) C₁₋₄alkyl (e.g.-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}.

(42) G₁ is a phenyl group, G₁ and Y may be fused together to form abenzofused aromatic or heteroaromatic system which might be optionallysubstituted by one or two substituents selected from: halogen, cyano,hydroxy, amide, ester, amino C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, SF₅.

It is to be understood that any two or more of the features inparagraphs (1) to (42) may be applied to any of the compounds of theformulae (I), (IA), (IB), (II), (IIA), (IIB), (III), (IIIA), (IIIB),(IV), (V), (VA) or (VB), or a pharmaceutically acceptable salt thereof.For example, the features of paragraph (41) for Y may be combined withany one of paragraphs (3) to (15) defining the group G.

As a further representative example paragraph (41) defining Y can becombined with any one of paragraphs (16) to (23). By way of a furtherexample Paragraphs (15), (22) and (41) may be combined. Othercombinations of two, three or four of paragraphs (1) to (42) are alsocontemplated.

Certain of the compounds of the invention may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof. Certain of the substituted heteroaromatic groups included incompounds of formula (I) may exist in one or more tautomeric forms.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The compounds of formula (I) mayreadily be isolated in association with solvent molecules bycrystallisation or evaporation of an appropriate solvent to give thecorresponding solvates.

In addition, prodrugs are also included within the context of thisinvention. As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher,S. Ramon and H. Barbra “Improved oral drug delivery: solubilitylimitations overcome by the use of prodrugs”, Advanced Drug DeliveryReviews (1996) 19(2) 115-130, each of which are incorporated herein byreference.

Prodrugs are any covalently bonded carriers that release a compound ofstructure (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own rightand/or be hydrolysable under in vivo conditions in the human body.Suitable pharmaceutically acceptable in vivo hydrolysable ester groupsinclude those which break down readily in the human body to leave theparent acid or its salt.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

Those skilled in the art will appreciate that in the preparation of thecompound of the invention or a solvate thereof it may be necessaryand/or desirable to protect one or more sensitive groups in the moleculeto prevent undesirable side reactions. Suitable protecting groups foruse according to the present invention are well known to those skilledin the art and may be used in a conventional manner. See, for example,“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.Alternatively a specific enantiomer of a compound of general formula (I)may be obtained by reacting the single specific enantiomer of theintermediate.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof. Certain of the substituted heteroaromatic groups included incompounds of formula (I) may exist in one or more tautomeric forms. Thepresent invention includes within its scope all such tautomeric forms,including mixtures.

Generally, and without being limited thereto, such compounds may havehigher oral bioavailability, and sometimes higher solubility and/orbrain penetrancy. Molecular weight here refers to that of the unsolvatedfree base compound, excluding any molecular weight contributed byaddition salts, solvent (e.g. water) molecules, prodrug molecular partscleaved off in vivo, etc.

In general, the compounds or salts of the invention should beinterpreted as excluding those compounds (if any) which are sochemically unstable, either per se or in water, that they are clearlyunsuitable for pharmaceutical use through all administration routes,whether oral, parenteral or otherwise. Such compounds are known to theskilled chemist. Prodrugs or compounds which are stable ex vivo andwhich are convertable in the mammalian (e.g. human) body to theinventive compounds are however included.

Example compounds of the present invention include a compound selectedfrom:

Ex. 1

-   (1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 2

-   (1R,3R or    1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 3

-   (1S,3S or    1R,3R)-5-(2-{[4-methyl-5-(4-methyl-¬1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}-ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 4

-   (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 5

-   (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 6

-   (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 7

-   (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 8

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 9

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 10

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 11

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 12

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 13

-   (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 14

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (TRANS);

Ex. 15

-   (1R,3R or 1S,    3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 16

-   (1S,3S or 1R,    3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 17

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane    (CIS);

Ex. 18

-   (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 19

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 20

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 21

-   (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 22

-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 23

-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 24

-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 25

-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 26

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 27

-   (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 28

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 29

-   (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 30

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 31

-   (1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 32

-   (1R,3S or    1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 33

-   (1S,3R or    1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 34

-   (1R,3S or    1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 35

-   (1S,3R or    1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 36

-   (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 37

-   (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 38

-   (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 39

-   (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 40

-   (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 41

-   (1R,3R or    1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 42

-   (1S,3S or    1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 43

-   (1R,3R or    1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 44

-   (1S,3S or    1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 45

-   (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 46

-   (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 47

-   (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 48

-   (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 49

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 50

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 51

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 52

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 53

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl})-propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 54

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 55

-   (1R,3S or    1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 56

-   (1S,3R or    1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 57

-   (1S,3S or    1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 58

-   (1R,3R or    1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 59

-   (1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 60

-   (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 61

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 62

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-¬1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 63

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 64

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 65

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 66

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 67

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 68

-   (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 69

-   (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 70

-   (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 71

-   (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 72

-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoro-methyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 73

-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 74

-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 75

-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 76

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 77

-   (1R,3R)-1-¬[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 78

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 79

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 80

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (CIS);

Ex. 81

-   (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 82

-   (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 83

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 84

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 85

-   (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl)}-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 86

-   (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 87

-   (1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 88

-   (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 89

-   (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 90

-   (1R,3R or    1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 91

-   (1S,3S or    1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 92

-   (1R,3R or    1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 93

-   (1S,3S or    1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 94

-   (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 95

-   (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 96

-   (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 97

-   (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 98

-   (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 99

-   1-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one    (CIS);

Ex. 100

-   1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one    (CIS, Enantiomer 1);

Ex. 101

-   1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one    (CIS);

Ex. 102

-   1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one    (CIS);

Ex. 103

-   3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one    (CIS, Enantiomer 1);

Ex. 104

-   3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one    (CIS, Enantiomer 1);

Ex. 105

-   (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 106

-   (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 107

-   1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}ethan-1-one    (CIS);

Ex. 108

-   4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl})    sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine (CIS);

Ex. 109

-   N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide    (CIS);

Ex. 110

-   N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl)}acetamide    (CIS, Enantiomer 1);

Ex. 111

-   N-{4-[4-methyl-5-({3-[(1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl)}acetamide    (CIS, Enantiomer 2);

Ex. 112

-   N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl)}acetamide    (CIS, Enantiomer 1);

Ex. 113

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 114

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 115

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 116

-   (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 117

-   (1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 118

-   (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 119

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one    (CIS, Enantiomer 1);

Ex. 120

-   1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one    (CIS, Enantiomer 1);

Ex. 121

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one    (CIS, Enantiomer 1);

Ex. 122

-   6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 123

-   6-[5-({3-[(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (TRANS);

Ex. 124

-   3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 125

-   3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 126

-   5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (TRANS);

Ex. 127

-   5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 128

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 129

-   5-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 130

-   5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 131

-   5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 132

-   5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (TRANS);

Ex. 133

-   1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 134

-   4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS);

Ex. 135

-   4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (TRANS);

Ex. 136

-   1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 137

-   1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 138

-   4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 139

-   4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one    (CIS, Enantiomer 1);

Ex. 140

-   (1S,3S/1R,3S)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 141

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 142

-   (1S,3S/1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 143

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane    (CIS);

Ex. 144

-   (1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 145

-   (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 146

-   (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 147

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 148

-   (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 149

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 150

-   (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 151

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 152

-   (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 153

-   (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 154

-   (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 155

-   (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 156

-   (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 157

-   (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 158

-   (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 159

-   (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 160

-   (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 161

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    (CIS);

Ex. 162

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 163

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane    (CIS);

Ex. 164

-   (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (TRANS);

Ex. 165

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 166

-   (1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 167

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 168

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 169

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 170

-   (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 171

-   (1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 172

-   (1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 173

-   (1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 174

-   (1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 175

-   (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl)}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 176

-   (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl)}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 177

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile    (CIS, Enantiomer 1);

Ex. 178

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile    (CIS, Enantiomer 1);

Ex. 179

-   5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (TRANS);

Ex. 180

-   5-[4-methyl-5-({3-[(1S,3S or    1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (TRANS, Enantiomer 1);

Ex. 181

-   5-[4-methyl-5-({3-[(1R,3R or    1S,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (TRANS, Enantiomer 2);

Ex. 182

-   5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS);

Ex. 183

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 184

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 185

-   5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyri    dine-2-carboxamide (CIS, Enantiomer 1);

Ex. 186

-   5-[5-({3-[(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 2);

Ex. 187

-   6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 188

-   6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylic    acid formate (CIS, Enantiomer 1);

Ex. 189

-   6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide    (CIS, Enantiomer 1);

Ex. 190

-   6-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide    (CIS, Enantiomer 1);

Ex. 191

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 192

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide    (CIS, Enantiomer 1);

Ex. 193

-   6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 194

-   N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 195

-   N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 196

-   N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 197

-   N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 198

-   5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 199

-   5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide    (CIS, Enantiomer 1);

Ex. 200

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 201

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 202

-   (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 203

-   (1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 204

-   (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 205

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 206

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 207

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 208

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 209

-   (1R,3R or    1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 210

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 211

-   (1R,3R or    1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 212

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 213

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 214

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 215

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 216

-   (1R,3R or    1S,R3)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 217

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 218

-   (1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 219

-   (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 220

-   (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 221

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane    (CIS);

Ex. 222

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 223

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 224

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 225

-   (1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 226

-   (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 227

-   (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 228

-   5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide    (CIS);

Ex. 229

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 230

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 231

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 232

-   (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 233

-   (1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 234

-   (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 235

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 236

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 237

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 238

-   (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 239

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 240

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 241

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 242

-   (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 243

-   (1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 244

-   (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 245

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 246

-   (1R,3S/1S,3R)    5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 247

-   (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 248

-   (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 249

-   (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 250

-   C(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 251

-   (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 252

-   (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 253

-   (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 2);

Ex. 254

-   (1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 255

-   (1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 256

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 257

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 258

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 259

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 260

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 261

-   (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 262

-   (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 263

-   (1R,3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 264

-   (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 265

-   (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 266

-   (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 267

-   (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 268

-   (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 269

-   (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 270

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 271

-   (1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 272

-   (1R,3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 273

-   (1R,3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 274

-   (1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 275

-   (1R,3S)-5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 276

-   (1R,3S)-5-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 277

-   (1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 278

-   (1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 279

-   (1R,3S)-5-[3-({4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 280

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide    (CIS, Enantiomer 1);

Ex. 281

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide    (CIS, Enantiomer 1);

Ex. 282

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile    (CIS, Enantiomer 1);

Ex. 283

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile    (CIS, Enantiomer 1);

Ex. 284

-   1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}ethan-1-one    (CIS, Enantiomer 1);

Ex. 285

-   4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzene-1-sulfonamide    (CIS, Enantiomer 1);

Ex. 286

-   2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetonitrile    (CIS, Enantiomer 1);

Ex. 287

-   2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetamide    (CIS, Enantiomer 1);

Ex. 288

-   3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide    (CIS, Enantiomer 1);

Ex. 289

-   3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide    (CIS, Enantiomer 1);

Ex. 290

-   2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide    (CIS, Enantiomer 1);

Ex. 291

-   1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]-heptan-5-yl}propan-2-ol    (CIS) diastereisomeric mixture;

Ex. 292

-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane    (CIS);

Ex. 293

-   (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane    (Enantiomer 1);

Ex. 294

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane    (Enantiomer 2);

Ex. 295

-   (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)-phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]-heptane    (Enantiomer 2);

Ex. 296

-   (1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)-phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 297

-   (1S,3S or    1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 298

-   (1R,3R or    1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 299

-   (1S,3S or    1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 300

-   (1R,3R or    1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 301

-   (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS);

Ex. 302

-   (1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (CIS, Enantiomer 1);

Ex. 303

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy})propyl)-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS);

Ex. 304

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy})propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 1);

Ex. 305

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy})propyl)-1-[4-(trifluoro-methyl)phenyl]-5-azaspiro[2.4]heptane    (TRANS, Enantiomer 2);

Ex. 306

-   (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane;

Ex. 307

-   (1S or    1R)-6-(3-{[4-methyl-¬5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane    (Enantiomer 1);

Ex. 308

-   (1R or    1S)-6-(3-{[4-methyl-5-¬(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane    (Enantiomer 2);

Ex. 309

-   (1S or    1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-¬4H-1,2,4-triazol-3-yl]sulfanyl}¬propyl)-1-phenyl-6-azaspiro[2.5]octane    (Enantiomer 1);

Ex. 310

-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (TRANS);

Ex. 311

-   (1R,3S or    1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (TRANS, Enantiomer 1);

Ex. 312

-   (1S,3R or    1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (TRANS, Enantiomer 2);

Ex. 313

-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (CIS);

Ex. 314

-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (CIS, Enantiomer 1);

Ex. 315

-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane    (CIS, Enantiomer 2);

Ex. 316

-   6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane;

Ex. 317

-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane:    (Diastereomer 1 Enantiomer 1);

Ex. 318

-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane:    (Diastereomer 1 Enantiomer 2);

Ex. 320

-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane:    (Diastereomer 2 Enantiomer 1);

Ex. 321

-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane:    (Diastereomer 2 Enantiomer 2);    or a pharmaceutically acceptable salt thereof.

Also provided is a compound selected from:

-   (1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    TRANS;-   (1R,3R or    1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1-   (1S,3S or    1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2-   (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    TRANS;-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S or    1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R or    1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    TRANS;-   (1R,3R or 1S,    3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or 1R,    3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    CIS;-   (1S,3R or 1R,    3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3S or 1S,    3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S or 1S,    3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane    hydrochloride, Enantiomer 2;-   (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    TRANS;-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1)-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    CIS;-   (1S,3S or    1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S or    1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    TRANS;-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3R or    1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or    1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S or    1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R or    1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S or    1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    TRANS;-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3R or    1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3S or    1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    CIS;-   (1S,3S or    1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S or    1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R or    1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S or    1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R    1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S or    1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    TRANS;-   (1R,3R or    1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or    1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3R or    1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3S or    1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    CIS;-   (1R,3S or    1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R or    1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3S or    1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1S,3R or    1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane,    Enantiomer 2;-   1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl}propan-2-ol,    CIS, diastereisomeric mixture;-   (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane    (CIS, E69);-   (1S,3S or    1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane,    Enantiomer 1;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1R,3R or    1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane,    Enantiomer 2;-   (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane;-   (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane;-   (1S or    1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane,    Enantiomer 1;-   (1R or    1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane,    Enantiomer 2;-   (1S or    1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane,    Enantiomer 1;-   1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    diastereoisomeric mixture;-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    Diastereomer 1 Enantiomer 1;-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    Diastereomer 1 Enantiomer 2;-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    Diastereomer 2, Enantiomer 1;-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    Diastereomer 2 Enantiomer 2;-   (1R,4S or 1S,4R or 1S,4S or    1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane,    Diastereisomer 1, Enantiomer 2;    or pharmaceutically acceptable salts thereof.

The present invention also provides a process for preparing a compoundof formula (I) or a salt thereof as defined above.

The process of the present invention for preparing compounds of formula(I) comprises the steps of: (a) reacting a compound of formula (VI):

wherein G is as defined for formula (I), with a compound of formula(VII):

X—(CHR)_(n)(CR₁R₂)_(m)(CR₁R₂)_(p)—W-G₁-Y   (VII)

wherein R, R₁, R₂, n, m, p, W, G₁ and Y are as defined for formula (I)and X is a leaving group or an aldehyde,

and thereafter optionally for process (a): (i) removing any protectinggroup(s); and/or (ii) forming a salt; and/or (iii) converting a compoundof formula (I) or a salt thereof to another compound of formula (I) or asalt thereof.

Process (a) may be performed using conventional methods for theformation of a tertiary amine. When X is a leaving group, it can behalogen such as chlorine. Alternatively X can be a sulfonyloxy groupsuch C₁₋₄alkylsulfonyloxy (e.g. methanesulfonyloxy),C₁₋₄alkylsulfonyloxy or haloC₁₋₄alkylsulfonyloxy (e.g.trifluoromethanesulfonyloxy); or arylsulfonyloxy wherein aryl isoptionally substituted phenyl, an optionally substituted 5- or6-membered heteroaromatic group, or an optionally substituted bicyclicgroup, for example optionally substituted phenyl, wherein in each casethe optional substituents are one or more C₁₋₂alkyl groups; e.g.para-toluenesulfonyloxy. When X is an halogen the reaction may becarried out using a base such as sodium carbonate in the presence of asource of iodide such as sodium iodide in a solvent such asN,N-dimethylformamide at a suitable temperature, e.g. 60° C.

When X is an aldehyde the reaction may be carried out using a reducingagent such as sodium triacetoxyborohydride in a suitable solvent such asdichloromethane or acetonitrile optionally in the presence of aceticacid or a Lewis acid in a catalytic amount and at a suitable temperaturesuch as room temperature.

In one aspect of the present invention there is provided syntheticprocesses for the preparation of compounds of formula (VI).

Compounds of formula (VI) where A and B form a 5-azaspiro[2.4]heptanesystem of formula (VIa)

may be synthesised with a process comprising the following Scheme 1:

wherein: Step a means the cycloropanation of (IX) to provide thebicyclic spiro imide (X); Step b means the reduction of imide (X) togive the tertiary benzyl amine (XI). Step c means the deprotection ofbenzyl amine (XI) to give compounds of formula (VIa).

Step a may be effected generating in situ the intermediate diazocompound to be reacted in a 1,3-dipolar cycloaddition with theappropriate double bond. In many cases this step is suitably performedapplying a procedure where hydrazone (VIII) is treated with an oxidizingagent, such as manganese dioxide, in a suitable solvent, such asdioxane, and at room temperature to form the diazocompound intermediatethat was then added to a solution of imide (IX) in a suitable solventsuch as dioxane. This is followed by allowing time to react asappropriate and a suitable workup.

Step b can be performed using a suitable reducing agent in a compatiblesolvent, such as Lithium aluminium hydride solution in THF, at anappropriate temperature, such as for example 68° C. This is followed bya suitable workup.

Step c consists of the deprotection of benzylamine using well knownprocedures, for example via hydrogenation refluxing a solution ofbenzylamine in a suitable solvent such as methanol in the presence of ahydrogen source such as ammonium formate and a hydrogenation catalystsuch as palladium on carbon. This is followed by allowing time to reactas appropriate and a suitable workup.

Compounds of formula (VIII) may be obtained using well known proceduresby reacting the corresponding aldehyde (XII) with hydrazine in asuitable solvent such as ethanol. This is followed by allowing time toreact as appropriate and a suitable workup.

Compound of formula (IX) may be obtained via Wittig reaction between theylide, generated in situ treating benzylmaleimide withtriphenylphosphine in acetic acid as solvent, with formaldehyde. This isfollowed by allowing time to react as appropriate and a suitable workup.

Compounds of formula (VI) where A and B form a 6-azaspiro[3.4]octanesystem of formula (VIb)

may be synthesised with a process comprises the Scheme 2:

wherein: Step a means double alkylation of malonate to form cyclobutane(XVI); Step b means mono decarboxylation of (XVI) to give thecorresponding monoester (XVII); Step c means alkylation of (XVII) togive the corresponding allyl derivative (XVIII); Step d means ozonolysisof allyl derivative (XVIII) to give the corresponding aldehyde (XIX);Step e means ring closure of (XIX) with benzylamine to give thecorresponding spiro lactam (XX); Step f means reduction of lactam (XX)to give the corresponding spiro amine (XXI); Step g means deprotectionof benzyl amine (XXI) to give compounds of formula (VIb).

Step a may be effected reacting dimethyl malonate with a dihalo compoundin the presence of a base such as sodium hydride in a solvent such asdioxane and at a temperature of 90° C. This is followed by allowing timeto react as appropriate and a suitable workup.

Step b can be carried out by thermic decarboxylation heating the diester(XVI) in a mixture of DMSO and water to reflux in the presence of saltssuch as LiCl. This is followed by allowing time to react as appropriateand a suitable workup.

Step c can be performed treating the cyclobutane monoesther (XVII) witha strong base such as Lithium bis(trimethylsilyl)amide and adding anallylhalide such as allylbromide in a suitable solvent such as THF at atemperature ranging between −78° C. and room temperature. This isfollowed by allowing time to react as appropriate and a suitable workup.

Step d may be performed via ozonlysis passing a stream of ozone inoxygen through a solution of allyderivative (XVIII) in a suitablesolvent such as dichloromethane at low temperature such as −78° C. Thisis followed by allowing time to react as appropriate and a suitableworkup.

Step e can be performed by first reacting the aldehyde (XIX) withbenzylamine in the presence of a reducing agent such as sodiumtriacetoxyborohydride in a suitable solvent such as THF at a temperaturesuch as room temperature. In a second time, after a suitable workup, theintermediate from reductive amination can be refluxed in a suitablesolvent such as THF in order to close the ring forming the spiro lactam(XX). This is followed by allowing time to react as appropriate and asuitable workup.

Step f can be performed using a suitable reducing agent in a compatiblesolvent, such as Lithium aluminium hydride solution in THF at anappropriate temperature, such as for example 68° C. This is followed bya suitable workup

Step g consists of deprotection of benzylamine using well knownprocedures for example via hydrogenation refluxing a solution ofbenzylamine derivative (XXI) in a suitable solvent such as methanol inthe presence of a hydrogen source such as ammonium formate and ahydrogenation catalyst such as palladium on carbon. This is followed byallowing time to react as appropriate and a suitable workup.

Compounds of formula (XV) may be obtained using well known procedures byfirst reacting the corresponding ketone with a reducing agent such assodium borohydride in a suitable solvent such as a mixture of ethanoland THF at a temperature ranging from −10° C. to −5° C. This is followedby allowing time to react as appropriate and a suitable workup. In asecond step the hydroxyl group may be converted into a bromide usingknown procedures such as treating it with hydrobromic acid at atemperature such as room temperature. This is followed by allowing timeto react as appropriate and a suitable workup.

Compounds of formula (VI) where A and B form a 6-azaspiro[2.5]octanesystem of formula (VIc)

may be synthesised analogously to what described in WO03091220 (A1) witha process comprises the following steps of Scheme 3:

wherein: Step a means Wittig reaction between Boc-piperidinone and asuitable triphenylphosphonium bromide (XXV); Step b meanscyclopropanation of the double bond of derivative (XXVI); Step c meansdeprotection of the amine (XXVII); Step d means protection astrifluoroacetamide of amine (XXVIII); Step e means reduction ofdichlorocyclopropane (XXIX); Step f means deprotection oftrifluoroacetamide (XXX) to give compounds of formula (VIc).

Step a may be effected treating a suitable triphenylphosphonium bromidewith a base such as sodium hydride in a suitable solvent such as THF ata temperature ranging from 0° C. to room temperature in order to formthe corresponding ylide to be reacted with N-Boc-piperidinone in asuitable solvent such as THF and at a temperature such as roomtemperature. This is followed by allowing time to react as appropriateand a suitable workup.

Step b can be carried out by reacting the double bond derivative (XXVI)with chloroform in the presence of a base such as sodium hydroxide and aphase transfer catalyst such as tetrabutylammoniumbromide. This isfollowed by allowing time to react as appropriate and a suitable workup.

Step c can be performed following well known procedures for the removalof Boc protecting group such as treating the protected compound with anacid such as trifluoroacetic acid in a suitable solvent such asdichloromethane at a temperature such as room temperature.

Step d can be carried out following well known procedures for protectionof amines as trifluoroacetic amides such as treating the aminederivative with trifluoroacetic anhydride in a suitable solvent such asdichloromethane. This is followed by allowing time to react asappropriate and a suitable workup.

Step e can be performed treating the dichlorocyclopropane derivativewith a reducing agent such as zinc powder in a suitable solvent such asa mixture of ethanol and water at a temperature ranging from 80° C. to95° C. This is followed by allowing time to react as appropriate and asuitable workup.

Step f consists of deprotection of trifluoroacetamide using well knownprocedures for example basic conditions such as treating the compoundwith a suitable base such as potassium carbonate in a suitable solventsuch as a mixture of methanol and water and at a temperature such asroom temperature. This is followed by allowing time to react asappropriate and a suitable workup.

Compounds of formula (XXV) may be obtained using well known proceduresby reacting the corresponding benzylbromides (XXXI) withtriphenylphosphine in a suitable solvent such as toluene at refluxtemperature. This is followed by allowing time to react as appropriateand a suitable workup.

Compounds of formula (VI) where A and B form a 5-azaspiro[2.5]octanesystem of formula (VId)

may be synthesised analogously to what described in Scheme 1 with aprocess comprises the following steps of Scheme 4:

wherein: Step a means the cycloropanation of (XXXII) to provide thebicyclic spiro imide (XXXIII); Step b means the reduction of imide(XXXIII) to give the tertiary benzyl amine (XXXIV). Step c means thedeprotection of benzyl amine (XXXIV) to give compounds of formula (VId).

Step a may be effected generating in situ the intermediate diazocompoundto be reacted in a 1,3-dipolar cycloaddition with the appropriate doublebond. In many cases this step is suitably performed applying a procedurewhere hydrazone (VIII) is treated with an oxidizing agent, such asmanganese dioxide, in a suitable solvent, such as dioxane, and at roomtemperature to form the diazocompound intermediate that was then addedto a solution of imide (XXXII) in a suitable solvent such as dioxane.This is followed by allowing time to react as appropriate and a suitableworkup.

Step b can be performed using a suitable reducing agent in a compatiblesolvent, such as Lithium aluminium hydride solution in THF, at anappropriate temperature, such as for example 68° C. This is followed bya suitable workup.

Step c consists of the deprotection of benzylamine using well knownprocedures, for example via hydrogenation refluxing a solution ofbenzylamine in a suitable solvent such as methanol in the presence of ahydrogen source such as ammonium formate and a hydrogenation catalystsuch as palladium on carbon. This is followed by allowing time to reactas appropriate and a suitable workup.

Compounds of formula (XXXII) may be obtained by reacting N-Benzylchloroacetamide (XXXV) with triphenylphosphine in a suitable solventsuch as toluene at reflux temperature, then treating the correspondingphosphonium chloride with methyl acrylate in the presence of a base suchas sodium methoxide, in a suitable solvent such as MeOH and at 0° C. Thephosphanylidene intermediate thus obtained may be reacted withformaldehyde in a suitable solvent, such as Toluene, and at a suitabletemperature, such as room temperature. This is followed by allowing timeto react as appropriate and a suitable workup.

A compound of formula (VII) may itself be prepared by reacting acompound of formula (XXXVII):

W-G₁-Y  (XXXVII)

Wherein G₁ and Y are as hereinbefore defined with a compound of formula(XXXVIII):

X—(CHR)_(n)(CR₁CR₂)_(m)(CR₁R₂)_(p)-L  (XXXVIII)

wherein X is defined as for formula (VII) and L is a leaving group,e.g., a bromine atom. For typical reaction conditions, see Preparation148 hereinafter.

A compound of formula (VII) wherein W is SO or SO₂ may itself beprepared by

(a) reacting a compound of formula (XXXIX):

S-G₁-Y  (XXXIX)

wherein G₁ and Y are as hereinbefore defined and S is a sulphur atomwith a compound of formula (XL):

X—(CHR)_(n)(CR₁CR₂)_(m)(CR₁R₂)_(p)-L  (XL)

wherein X is defined as for formula (VI) and L is a leaving group, e.g.,a bromine atom. For typical reaction conditions, see Preparation 148hereinafter.

(b) oxydizing the sulphur with an appropriate oxydizing agent such asoxone or m-chloroperbenzoic acid in a suitable solvent such asdichloromethane.

Compounds of formula (I) wherein W is oxygen and G, R, R₁, R₂, n, m, p,G₁ and Y are as defined as above, may be prepared by reacting a compoundof formula (XL):

wherein G, R, R₁, R_(2,n), m and p are as defined for formula (I), witha compound of formula (XLI):

X-G₁-Y  (XLI)

wherein G₁ and Y are as hereinbefore defined and X is a leaving groupsuch as methyl sulphone. For typical reaction conditions see Example303.

Interconversion reactions between compounds of formula (I) and saltsthereof may be performed using methods well known in the art.

Compounds of formula (I) have been found to exhibit affinity fordopamine receptors, in particular the D₃ receptor, and are expected tobe useful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions.

Such affinity is typically calculated from the IC₅₀ as the concentrationof a compound necessary to displace 50% of the radiolabeled ligand fromthe receptor, and is reported as a “K_(i)” value calculated by thefollowing equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L=radioligand and K_(D)=affinity of radioligand for receptor(Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

In the context of the present invention pKi (corresponding to theantilogarithm of Ki) is used instead of Ki and the compounds of thepresent invention typically show pKi greater than 7. In one aspect thepresent invention provides compounds of formula (I) having a pKicomprised between 7 and 8. In another aspect the present inventionprovides compounds of formula (I) having a pKi comprised between 8 and9. In a further aspect the present invention provides compounds offormula (I) having a pKi greater than 9.

Many of the compounds of formula (I) have also been found to havegreater affinity for dopamine D₃ than for D₂ receptors. The therapeuticeffect of currently available antipsychotic agents (neuroleptics) isgenerally believed to be exerted via blockade of D₂ receptors; howeverthis mechanism is also thought to be responsible for undesirableextrapyramidal side effects (eps) associated with many neurolepticagents. It has been suggested that blockade of the recentlycharacterised dopamine D₃ receptor may give rise to beneficialantipsychotic activity without significant eps. (see for exampleSokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, ClinicalNeuropharmacology, Vol 16, No. 4, 295-314, 1993). In one embodimentcompounds of the present invention are provided which have higher (e.g.≥10× or ≥100× higher) affinity for dopamine D₃ than dopamine D₂receptors (such affinity can be measured using standard methodology forexample using cloned dopamine receptors—see herein). Said compounds maysuitably be used as selective modulators of D₃ receptors.

From the localisation of D₃ receptors, it could also be envisaged thatthe compounds could also have utility for the treatment of substanceabuse where it has been suggested that D₃ receptors are involved (e.g.see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of suchsubstance abuse include alcohol, cocaine, heroin and nicotine abuse.Other conditions which may be treated by the compounds includedyskinetic disorders such as Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias; depression; anxiety, cognitiveimpairment including memory disorders such as Alzheimers disease, eatingdisorders, sexual dysfunction, premature ejaculation, sleep disorders,emesis, movement disorders, obsessive-compulsive disorders, amnesia,aggression, autism, vertigo, dementia, circadian rhythm disorders andgastric motility disorders e.g. IBS.

Compounds of formula (I) may be used for treatment of all aspects ofdrug dependency including withdrawal symptoms from drugs of abuse suchas alcohol, cocaine, opiates, nicotine, benzodiazepines and inhibitionof tolerance induced by opioids. In addition, compounds of formula (I)and pharmaceutically acceptable salts and solvates thereof may be usedto reduce craving and therefore will be useful in the treatment of drugcraving. Drug craving can be defined as the incentive motivation toself-administer a psychoactive substance that was previously consumed.

Three main factors are involved in the development and maintenance ofdrug craving: (1) Dysphoric states during drug withdrawal can functionas a negative reinforcer leading to craving; (2) Environmental stimuliassociated with drug effects can become progressively more powerful(sensitization) in controlling drug seeking or craving, and (3) Acognition (memory) of the ability of drugs to promote pleasurableeffects and to alleviate a dysphoric state during withdrawal. Cravingmay account for the difficulty that individuals have in giving up drugsof abuse and therefore contributes significantly to the development andmaintenance of drug dependence.

The compounds of formula (I) are of potential use as antipsychoticagents for example in the treatment of schizophrenia, schizo-affectivedisorders, psychotic depression, mania, paranoid and delusionaldisorders. Furthermore, they could have utility as adjunct therapy inParkinsons Disease, particularly with compounds such as L-DOPA andpossibly dopaminergic agonists, to reduce the side effects experiencedwith these treatments on long term use (e.g. see Schwartz et al., BrainRes. Reviews, 1998, 26, 236-242).

Within the context of the present invention, the terms describing theindications used herein are classified in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, published by the AmericanPsychiatric Association (DSM-V). The various subtypes of the disordersmentioned herein are contemplated as part of the present invention.

Within the context of the present invention, the term “schizophreniaspectrum and other psychotic disorder” includes: Schizotypal(personality disorder; Delusional Disorder; Brief Psychotic Disorder;Schizopreniform Disorder; Schizophrenia; Schizoaffective Disorder;Substance/Medication-Induced Psychotic Disorder; Psychotic Disorder dueto another Medical Condition.

Within the context of the present invention, the term “catatonia”includes: Catatonia Associated With Another Mental Disorder (CatatoniaSpecifier); Catatonic Disorder Due to another Medical Condition;Unspecified Catatonia; Other Specified Schizophrenia Spectrum and otherPsychotic Disorder; Unspecified Schizophrenia Spectrum and otherPsychotic Disorder.

Within the context of the present invention, the term“obsessive-compulsive disorder” includes: Obsessive Compulsive Disorder;Body Dismorphic Disorder; Hoarding Disorder; Trichotillomania(Hair-Pulling Disorder); Excoriation (Skin-Picking) Disorder;Substance/Medication-Induced Obsessive-Compulsive and Related Disorder;Obsessive-Compulsive and Related Disorder due to Another MedicalCondition; Other Specified Obsessive-Compulsive and Related Disorders;Unspecified Obsessive-Compulsive and Related Disorders.

Within the context of the present invention, the term “feeding andeating disorders” includes: Pica; Ruminant Disorder;Avoidant/Restrictive Food Intake Disorder; Anorexia Nervosa; BulimiaNervosa; Binge-Eating Disorder; Other Specified Feeding or eatingDisorder; Unspecified Feeding or Eating Disorder.

Within the context of the present invention, the term “sexualdisfunctions” includes: Delayed ejaculation; Erectile Disorder; FemaleOrgasmic Disorder; Female Sexual Interest/Arousal Disorder;Genito-Pelvic Pain/Penetration Disorder; Male Hypoactive Sexual DesireDisorder; Premature (early) Ejaculation; Substance/Medication-InducedSexual Dysfunction; Unspecified Sexual Dysfunction.

Within the context of the present invention, the term “substance-relateddisorders and addictive disorders” includes: Substance-Related Disorderssuch as Substance Use Disorders; Substance-Induced Disorders; SubstanceIntoxication and Withdrawal; Substance/Medication-Induced MentalDisorders; Alcohol-Related Disorders such as Alcohol Use Disorder:Alcohol Intoxication; Alcohol Withdrawal; Other Alcohol-InducedDisorders; Unspecified Alcohol-Related Disorders; Caffeine-RelatedDisorders such as Caffeine Intoxication; Caffeine Withdrawal; OtherCaffeine-Induced Disorders; Unspecified Caffeine-Related Disorders;Cannabis-Related Disorders such as Cannabis Use Disorder: CannabisIntoxication; Cannabis Withdrawal; Other Cannabis-Induced Disorders;Unspecified Cannabis-Related Disorders; Hallucinogen-Related Disorderssuch as Phencyclidine Use Disorder; Other Hallucinogen Use Disorder;Phencyclidine Intoxication; Other Hallucinogen Intoxication;Hallucinogen Persisting Perception Disorder; Other Phencyclidine-InducedDisorders; Other Hallucinogen-Induced Disorders UnspecifiedPhencyclidine-Related Disorders; Unspecified Hallucinogen-RelatedDisorders; Inhalant-Related Disorders such as Inhalant Use Disorder:Inhalant Intoxication; Other Inhalant-Induced Disorders; UnspecifiedInhalant-Related Disorders; Opioid-Related Disorders such as Opioid UseDisorder; Opioid Intoxication; Opioid Withdrawal; Other Opioid-InducedDisorders; Unspecified Opioid-Related Disorders; Sedative-, Hypnotic-,or Anxiolytic-Related Disorders such as Sedative-, Hypnotic-, orAnxiolytic Use Disorder: Sedative-, Hypnotic-, or AnxiolyticIntoxication; Sedative-, Hypnotic-, or Anxiolytic Withdrawal; OtherSedative-, Hypnotic-, or Anxiolytic-Induced Disorders; UnspecifiedSedative-, Hypnotic-, or Anxiolytic-Related Disorders; Stimulant-RelatedDisorders such as Stimulant Use Disorder; Stimulant Intoxication;Stimulant Withdrawal; Other Stimulant-Induced Disorders; UnspecifiedStimulant-Related Disorders; Tobacco-Related Disorders such as TobaccoUse Disorder; Tobacco Intoxication; Tobacco Withdrawal; OtherTobacco-Induced Disorders; Unspecified Tobacco-Related Disorders; Other(or Unknown) Substance-Related Disorders such as Other (or Unknown)Substance Use Disorder; Other (or Unknown) Substance Intoxication; Other(or Unknown) Substance Withdrawal; Other (or Unknown) Substance-InducedDisorders; Unspecified Other (or Unknown) Substance-Related Disorders.

Within the context of the present invention, the term“non-substance-related disorders and addictive disorders” includes:Gambling Disorders.

In a further aspect therefore the present invention provides a method oftreating a condition for which modulation (especiallyantagonism/inhibition) of dopamine receptors (especially dopamine D₃receptors) is beneficial, which comprises administering to a mammal(e.g. human) in need thereof an effective amount of a compound offormula (I) or a pharmaceutically (i.e physiologically) acceptable saltthereof. Such conditions in particular include psychoses/psychoticconditions such as schizophrenia, and substance abuse.

The invention also provides the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a condition in a mammal for whichmodulation (especially antagonism/inhibition) of dopamine receptors(especially dopamine D₃ receptors) is beneficial.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of acondition in a mammal for which modulation (especiallyantagonism/inhibition) of dopamine receptors (especially dopamine D₃receptors) is beneficial.

In one embodiment, D₃ antagonists according to the present invention areused in the treatment of psychoses such as schizophrenia or in thetreatment of substance abuse.

Thus, a still further aspect the invention provides a method of treatinga psychotic condition (e.g. schizophrenia) or substance abuse whichcomprises administering to a mammal (e.g. human) in need thereof aneffective amount of a compound of formula (I) as herein defined or apharmaceutically acceptable salt thereof.

Also provided is the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a psychotic condition (e.g.schizophrenia) or substance abuse in a mammal.

Also provided is a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the treatment of a psychoticcondition (e.g. schizophrenia) or substance abuse in a mammal.

Also provided is a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use as an active therapeutic substance in amammal, e.g. for use in the treatment of any of the conditions describedherein.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceutically(i.e physiologically) acceptable salt thereof and a pharmaceutically(i.e physiologically) acceptable carrier. The pharmaceutical compositioncan be for use in the treatment of any of the conditions describedherein.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as liquids orsolids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol oranoil. The formulation may also contain a suspending agent,preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluoro-chlorohydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

In one embodiment, the composition is in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 1 to250 mg (and for parenteral administration contains for example from 0.1to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, for example between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, forexample between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof calculated as the free base, the compound being administered 1to 4 times per day. Suitably the compounds will be administered for aperiod of continuous therapy, for example for a week or more.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

In the procedures that follow, after each starting material, referenceto a Preparation or Example by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

Were reference is made to the use of a “similar or analogous or as”procedure, as will be appreciated by those skilled in the art, suchprocedure may involve minor variation, for example reaction temperature,reagent/solvent amount, reaction time, work-up conditions orchromatographic purification conditions.

In the procedures that follow, the absolute stereochemistry “up” or“down” configurations in the structures are to be considered correct ifaccompanied by a single absolute stereochemistry assignment in the name(for example(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane). On thecontrary, the absolute stereochemistry “up” or “down” configurations inthe structures are to be considered arbitrarily assigned with the onlyaim to distinguish one enantiomer from the other if not accompanied by asingle absolute stereochemistry assignment in the name (for example(1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane).

All temperatures refer to ° C.

Proton Magnetic Resonance (NMR) spectra may be typically recorded eitheron Varian instruments at 400 or 500 MHz, or on a Bruker instrument at400 MHz.

Chemical shifts are expressed in parts of million (ppm, δ units).Chemical shifts are reported in ppm downfield (δ) from Me₄Si, used asinternal standard, and are typically assigned as singlets (s), broadsinglets (br.s.), doublets (d), doublets of doublets (dd), doublets ofdoublets of doublets (ddd), doublets of triplets (dt), triplets (t),triplets of doublets (td), quartets (q), or multiplets (m).

LCMS may be recorded under the following conditions: DAD chromatographictraces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MSAcquity™ system coupled with Micromass ZQ™ or Waters SQD singlequadrupole mass spectrometer operated in positive and/or negative ESionisation mode. The QC methods used were two, one operated under low pHconditions and another one operated under high pH conditions. Details ofthe method operated under low pH conditions were: column, Acquity BEHC₁₈, 1.7 m, 2.1×50 mm or Acquity CSH C₁₈, 1.7 m, 2.1×50 mm, thetemperature column was 40° C.; mobile phase solvent A was milliQwater+0.1% HCOOH, mobile phase solvent B MeCN+0.1% HCOOH. The flow ratewas 1 ml/min. The gradient table was t=0 min 97% A-3% B, t=1.5 min 0.1%A-99.9% B, t=1.9 min 0.1% A-99.9% B and t=2 min 97% A-3% B. The UVdetection range was 210-350 nm and the ES⁺/ES⁻ range was 100-1000 amu.

Details of the method operated under high pH conditions were the same ofthose listed above for the low pH method apart from: column Acquity BEHC₁₈, 1.7 m, 2.1×50 mm; mobile phase solvent A was 10 mM aqueous solutionof NH₄HCO₃ adjusted to pH=10 with ammonia, mobile phase solvent B MeCN.

Semipreparative mass directed autopurifications (MDAP) were carried outusing Waters Fractionlynx™ systems operated under low or high pHchromatographic conditions. The stationary phases used were, XTerra C18,XBridge C18, Sunfire C18, XSelect C18, Gemini AXIA C18. The length ofthe columns was 5, 10 or 15 cm, while the internal diameter was 19, 21or 30 mm. The particle size of the stationary phases was 5 or 10 μm. Thepurifications were carried out using low pH or high pH chromatographicconditions. The mobile phase solvent composition was the same used forQC analysis. The combinations stationary/mobile phases used were:XTerra, XBridge, Sunfire, XSelect—low pH mobile phases and XTerra,XBridge, Gemini AXIA—high pH mobile phases. All the purifications werecarried out with the column kept at room T. The flow rate used was 17 or20 ml/min for columns of internal diameter 19 or 21 mm and 40 or 43ml/min for columns of internal diameter 30 mm. The trigger for thecollection of the target species was the presence of the target m/zratio value in the TIC MS signal. The gradient timetable was customisedon the Rt behaviour of the target species.

Purification may also be performed using Biotage® Isolera or Biotage®SP1 flash chromatography systems, these instruments work with Biotage®KP-SIL cartridges, Biotage® KP-NH cartridges or Biotage® KP-C18cartridges.

Unless otherwise stated, all reactions are typically performed underinert atmosphere (for example under Nitrogen).

TLC refers to thin layer chromatography on silica plates, and driedrefers to a solution dried over anhydrous sodium sulphate,

The following abbreviations are used in the text: EtOAc, AcOEt, EA=ethylacetate; Et₂O=diethyl ether; MeOH=methanol; THF=tetrahydrofuran; r.t.(RT) refers to room temperature; DMSO=dimethyl sulfoxide;DMF=N,N′-dimethylformamide; DCM=dichloromethane; EtOH=ethanol;DCE=dichloroethane; DME=1,2-Dimethoxyethane; Cy, cHex=cyclohexane;ACN=Acetonitrile; tBuOH=tert-Butanol; TEA=triethylamine;DIPEA=N,N-Diisopropylethylamine; Boc₂O=Di-tert-butyl dicarbonate;TFA=trifluoroacetic acid;Pd₂(dba)₃=Tris(dibenzylideneacetone)dipalladium(0);TPP=triphenylphosphine; AcOH=acetic acid; LAH=Lithium aluminum hydride;T3P=Propylphosphonic anhydride; SCX Cartridge=Strong Cation ExchangeCartridge; ipa=isopropylamine; FA=formic acid; Py=pyridine;TBAF=Tetrabutylammonium fluoride; TBDMSCl=tert-Butyldimethylsilylchloride; HOBt*H₂O=1-Hydroxybenzotriazole hydrate;EDC*HCl=N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride;DMAP=4-(Dimethylamino)pyridine; TMSCN=Trimethylsilyl cyanide;mCPBA=3-Chloroperbenzoic acid; mCBA=3-Chlorobenzoic acid; CbzCl=Benzylchloroformate; ACE-Cl=1-Chloroethyl chloroformate.

Preparation 1: {[4-(trifluoromethyl)phenyl]methylidene}hydrazine

To a solution of hydrazine hydrate (6.4 mL, 86.1 mmol) in EtOH (25 mL)4-(trifluoromethyl)benzaldehyde (3.92 mL, 28.7 mmol) was added dropwiseunder nitrogen over 10 min. The resulting solution was stirred at RT for1 h. The solution was cooled down to RT, then diluted with water andDCM. Phases were separated; organic one was dried and concentrated underreduced pressure affording{[4-(trifluoromethyl)phenyl]methylidene}hydrazine (p1, 5.2 g, y=96%) aspale yellow oil that was used as such in the next step. MS (m/z): 189.2[MH]⁺

Preparation 2: (phenylmethylidene)hydrazine

To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL)benzaldehyde (1.04 mL, 10 mmol) was added dropwise under nitrogen over10 min. The resulting solution was stirred at RT for 1.5 h. After thistime, water was added and ethanol was evaporated under vacuum. Theaqueous phase was extracted with DCM (×4). Combined organics were driedand concentrated to obtain (phenylmethylidene)hydrazine (p2, 1.2 g,y=quant.) as yellow oil. MS (m/z): 121.1 [MH]⁺

Preparation 3: [2-fluoro-4-(trifluoromethyl)phenyl]methylidene hydrazine

To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL)2-fluoro-4-(trifluoromethyl)benzaldehyde (1.36 mL, 10 mmol) was addeddropwise under nitrogen over 10 min. The resulting solution was stirredat reflux for 1 h, then cooled down to RT in 1 h. After this time, waterwas added and the aqueous phase was extracted with DCM (×4). Combinedorganics were dried and concentrated to obtain[2-fluoro-4-(trifluoromethyl)phenyl]methylidene}hydrazine (p3, 2.15 g,y=quant.) as yellow liquid. MS (m/z): 207.3 [MH]⁺

Preparation 4: [(2,4-difluorophenyl)methylidene]hydrazine

To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL)2,4-difluorobenzaldehyde (1.09 mL, 10 mmol) was added dropwise. Theresulting solution was stirred at RT for 1 h, then water was added andthe aqueous phase was extracted with DCM (×4). Combined organics weredried and concentrated to obtain[(2,4-difluorophenyl)methylidene]hydrazine (p4, 1.8 g, y=quant.) aswhite solid. NMR: ¹H NMR (DMSO-d₆) δ: 7.81 (s, 1H), 7.70-7.78 (m, 1H),7.21 (d, 1H), 7.08 (s, 2H), 7.05 (d, 1H)

Preparation 5: [(4-fluorophenyl)methylidene]hydrazine

To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL)4-fluorobenzaldehyde (1.07 mL, 10 mmol) was added dropwise. Theresulting solution was stirred at reflux for 1 h, then cooled down toRT. After this time, water was added and the aqueous phase was extractedwith DCM (×4). Combined organics were dried and concentrated to obtain[(4-fluorophenyl)methylidene]hydrazine (p5, 1.5 g, y=quant.) as yellowwax. NMR: ¹H NMR (DMSO-d₆) δ: 7.71 (s, 1H), 7.47-7.55 (m, 2H), 7.15 (m,2H), 6.75 (s, 2H)

Preparation 6: [(3,5-dichlorophenyl)methylidene]hydrazine

To a solution of hydrazine hydrate (0.72 mL, 8.55 mmol) in EtOH (6 mL)3,5-dichlorobenzaldehyde (1 g, 5.7 mmol) was added portionwise undernitrogen over 5 min. The resulting solution was stirred at RT for 3 hrs.The solution was evaporated, and the residue was partitioned between DCMand water and extracted several times with DCM. The combined organicphases were washed with brine (15 mL), dried, filtered, and evaporatedto yield a yellow solid that was purified by FC on silica gel (elutingfrom cHex to 30% EtOAc) to afford[(3,5-dichlorophenyl)methylidene]hydrazine (p6, 510 mg, y=47%) as yellowsolid. NMR: ¹H NMR (DMSO-d₆) δ:7.62 (s, 1H), 7.48 (d, 2H), 7.38-7.43 (m,1H), 7.25 (s, 2H)

Preparation 7: {[2-(trifluoromethyl)phenyl]methylidene}hydrazine

To a solution of hydrazine hydrate 60% in water (2.1 mL, 25.8 mmol) inEtOH (7.5 mL) 2-(trifluoromethyl)benzaldehyde (1.13 mL, 8.6 mmol) wasadded dropwise, under nitrogen, over 10 min. The resulting solution wasstirred at RT for 1.5 h. After this time, water was added and theaqueous phase was extracted with DCM (×3). Combined organics were driedand concentrated to obtain{[2-(trifluoromethyl)phenyl]methylidene}hydrazine (p7, 1.31 g, y=71%) asyellow oil. NMR: ¹H NMR (DMSO-d₆) δ: 8.01 (d, 1H), 7.89-7.96 (m, 1H),7.65 (d, 1H), 7.59 (m, 1H), 7.34-7.43 (m, 3H)

Preparation 8:{[4-fluoro-2-(trifluoromethyl)phenyl]methylidene}hydrazine

To a solution of hydrazine hydrate (1.9 mL, 23.4 mmol) in EtOH (7.5 mL)4-fluoro-2-(trifluoromethyl)benzaldehyde (1.07 mL, 7.8 mmol) was addeddropwise under nitrogen over 10 min. The resulting solution was stirredat RT for 1 h. After this time, water was added and the aqueous phasewas extracted with DCM (×3). Combined organics were dried andconcentrated to obtain{[4-fluoro-2-(trifluoromethyl)phenyl]methylidene}hydrazine (p8, 1.81 g,y=98%) as pale yellow solid. NMR: ¹H NMR (DMSO-d₆) δ: 8.03 (m, 1H), 7.89(m, 1H), 7.54 (m, 1H), 7.48 (d, 1H), 7.39 (s, 2H)

Preparation 9: 5-methanehydrazonoyl-2-(trifluoromethyl)pyridine

To a solution of hydrazine hydrate (0.48 mL, 5.7 mmol) in EtOH (5 mL)6-(trifluoromethyl)-3-pyridinecarboxaldehyde (1 g, 5.7 mmol) was addedportionwise under nitrogen over 5 min. The resulting solution wasstirred at RT for 3 hrs. The solution was evaporated, and the residuewas partitioned between DCM and water and extracted several times withDCM. The combined organic phases were washed with brine (15 mL), dried,filtered, and evaporated to yield5-methanehydrazonoyl-2-(trifluoromethyl)pyridine (p9, 0.87 g, y=quant.)as a white solid that was used as such in the next step. MS (m/z): 190.4[MH]⁺

Preparation 10: 1-benzyl-3-methylidenepyrrolidine-2,5-dione

1-benzyl-2,5-dihydro-1H-pyrrole-2,5-dione (25 g, 134 mmol) was dissolvedin AcOH (80 mL) and PPh₃ (35 g, 134 mmol) was added. The resultingsolution was stirred for 1 h at RT then formaldehyde 37% in water (15mL, 252 mmol) was added. The solution was stirred at RT for 2.5 hrs.Volatiles were removed under reduced pressure. The residue waspartitioned between water (300 mL) and DCM (350 mL). The layers wereseparated and the organic portion was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified byFC on silica gel (eluent: cyclohexane-EtOAc, 80:20 to 60:40) affording1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 24.44 g, y=90%) ascolorless oil. MS (m/z): 202.2 [MH]⁺.

Preparation 11 and 12:(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p1) and(1S,3R/1R,3S)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, p12)

To a solution of {[4-(trifluoromethyl)phenyl]methylidene}hydrazine (p1,11.29 g, 60 mmol) in dioxane (65 mL) at 10° C., MnO₂ (52.16 g, 600 mmol)was added portionwise. The resulting mixture was stirred at RT for 1 h,then it was filtered over a pad of Celite washing with dioxane (70 mL).This pale yellow solution was then added into a solution of1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 12.07 g, 60 mmol) indioxane (30 mL). The resulting orange/red solution was left stirring atRT for 40 hrs. Solvent was removed and the residue was purified by FC onsilica gel (eluent: from cHex to 30% EtOAc) to afford:(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p11): 7.2 g, y=33%, 96% purity and(1S,3R/1R,3S)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p12): 7.5 g, y=35%, 60% purity, that were usedas such in the next step. MS (m/z): 360.3 [MH]⁺.

Preparation 13:(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS)

Step a:(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p11, 0.91 g, 2.53 mmol) was dissolved in THF(15 mL) and LiAlH₄ 1M in THF (5.06 mL, 5.06 mmol) was added dropwise.The resulting orange solution was heated at reflux for 1 h. Then it wascooled with an ice bath and quenched with Na₂SO₄*10 H₂O until gasevolution ceased. The mixture was filtered over a pad of Celite washingwith EtOAc, and the solution was concentrated to afford(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, 810 mg) as oil that was used as such in the next step.

Step b:(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, 810 mg from step a) was dissolved in MeOH (20 mL) under N₂ andammonium formate (1.55 g, 24.4 mmol) was added. After 2 cycles vacuum/N₂Pd/C (0.25 g) was added. The resulting mixture was stirred at reflux for1 h. After cooling down to RT, it was filtered over a pad of Celite, thesolvent was evaporated and the residue was charged on SCX cartridge(eluting with 1N NH₃ in MeOH) to afford, after evaporation,(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 495 mg, y=81%) as pale yellow oil. MS (m/z): 242.3 [MH]⁺.

Preparation 14:(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS)

Step a:(1S,3R/1R,3S)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p12, 7.5 g, 20.87 mmol) was dissolved in THF(120 mL) and LiAlH₄ 1M in THF (15.65 mL, 15.65 mmol) was added dropwiseat 0° C. The resulting orange solution was heated at reflux for 1 h.Then it was cooled with an ice bath and quenched with Na₂SO₄*10 H₂Ountil gas evolution ceased. The mixture was filtered over a pad ofCelite washing with EtOAc, and the solution was concentrated to afford(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, 6.9 g) as oil that was used as such in the next step.

Step b:(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, 6.9 g, from step a) was dissolved in MeOH (200 mL) under N₂ andammonium formate (6.58 g, 104.35 mmol) was added. Then Pd/C (800 mg) wasadded. The resulting mixture was stirred at reflux for 5 hrs. Aftercooling it was filtered over a pad of Celite, the solvent was evaporatedand 12 mL of HCl ˜1.25M in MeOH were added. Solvent was eliminated underreduced pressure and the residue was loaded on a SCX cartridge washingwith MeOH and eluting with NH₃ 1M in MeOH. Solvent was eliminated underreduced pressure affording(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 3.89 g, y=77%). MS (m/z): 242.0 [MH]⁺.

Preparation 15:(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1)

(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 3.89 g) was submitted to chiral Prep HPLC (SFC) to separateenantiomers:

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Ethanol + 0.1%isopropylamine) 7% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.)  38 DAD detection 220 nm Loop 900 μL Injection 53.3mg/injection

affording: (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p15, 1.5 g). Enantiomer 1: Ret. Time 6.4 min, 100% ee. MS (m/z):242.0 [MH]⁺.

Preparation 16 and 17:(1S,3S/1R,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione (TRANS,p16) and(1R,3S/1S,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione (CIS,p17)

To a solution of (phenylmethylidene)hydrazine (p2, 0.6 g, 5 mmol) indioxane (10 mL) at 10° C., MnO₂ (4.4 g, 50 mmol) was added portionwise.The resulting mixture was stirred at RT for 30 min, then it was filteredover a pad of Celite washing with dioxane and this solution was added toa solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 1 g, 5mmol) in dioxane (3.5 mL). The resulting orange/red solution was leftstirring at RT O/N. Solvent was removed and the residue was purified byFC on silica gel (eluent: from cHex to 30% EtOAc) to afford:(1S,3S/1R,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p16): 524 mg, y=36%, 70% purity and 171 mg,y=12%, 90% purity, and(1R,3S/1S,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p17): 550 mg, y=38%, 76% purity, that were usedas such in the next step. MS (m/z): 292.2 [MH]⁺.

Preparation 18: (1S,3S/1R,3R)-1-phenyl-5-azaspiro[2.4]heptane (TRANS)

The compound was synthesized in analogy to the method described forPreparation 13 starting from(1S,3S/1R,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione (TRANS,p16, 524 mg, 1.8 mmol) and affording(1S,3S/1R,3R)-1-phenyl-5-azaspiro[2.4]heptane (p18, TRANS, 166 mg, 60%purity). MS (m/z): 242.3 [MH]⁺.

Preparation 19: (1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS)

The compound was synthesized in analogy to the method described forPreparation 13 starting from(1R,3S/1S,3R)-5-benzyl-1-phenyl-5-azaspiro[2.4]heptane-4,6-dione (p17,CIS, 1.13 g, 3.88 mmol) and affording(1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (p19, CIS, 42 mg, y=6%).MS (m/z): 174.1 [MH]⁺.

Preparation 20 and 21:(1R,3S/1S,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p20) and(1S,3S/1R,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, p21)

To a solution of{[2-fluoro-4-(trifluoromethyl)phenyl]methylidene}hydrazine (p3, 1.05 g,5 mmol) in dioxane (10 mL) at 10° C., MnO₂ (4.4 g, 50 mmol) was addedportionwise. The resulting mixture was stirred at RT for 30 min, then itwas filtered over a pad of Celite washing with dioxane (10 mL) directlyinto a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 1g, 5 mmol) in dioxane (10 mL). The resulting orange/red solution wasleft stirring at RT O/N. Solvent was removed and the residue waspurified by FC on Si cartridge (eluent: from cHex to 30% EtOAc) toafford:(1R,3S/1S,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p20): 1.12 g, 55% purity and(1S,3S/1R,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p21): 518 mg, 86% purity, that were used assuch in the next step. MS (m/z): 378.3 [MH]⁺.

Preparation 22:(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro-[2.4]heptane(TRANS)

The compound was synthesized in analogy to the method described forPreparation 13 starting from(1R,3S/1S,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(p20, TRANS, 1.2 g, 3.18 mmol) and affording(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p22, TRANS, 308 mg, y=37%). MS (m/z): 260.2 [MH]⁺.

Preparation 23:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro-[2.4]heptane(CIS)

The compound was synthesized in analogy to the method described forPreparation 14 starting from(1S,3S/1R,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(p21, CIS, 0.654 g, 1.73 mmol) and affording(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p23, CIS, 234 mg, y=52%). MS (m/z): 260.2 [MH]⁺.

Preparation 24 and 25:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p24, CIS, Enantiomer 1) and(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p25, CIS, Enantiomer 2)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(prepared as in p23, CIS, 1 g) was submitted to chiral Prep HPLC (SFC)to separate enantiomers:

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Ethanol + 0.1%isopropylamine) 7% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.)  38 DAD detection 220 nm Loop 500 μL Injection 25mg/injection

affording:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p24, CIS, 351 mg), Enantiomer 1: Ret. Time 4.7 min, 100% ee. MS (m/z):260.2 [MH]⁺, and(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p25, CIS, 378 mg), Enantiomer 2: Ret. Time 6.2 min, 98.8% ee. MS (m/z):260.2 [MH]⁺.

Preparation 26 and 27:(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p26) and(1S,3S/1R,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(CIS, p27)

To a solution of [(2,4-difluorophenyl)methylidene]hydrazine (p4, 0.78 g,5 mmol) in dioxane (10 mL) at 10° C., MnO₂ (4.4 g, 50 mmol) was addedportionwise. The resulting mixture was stirred at RT for 30 min, then itwas filtered over a pad of Celite washing with dioxane (10 mL) directlyinto a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 1g, 5 mmol) in dioxane (10 mL). The resulting orange/red solution wasleft stirring at RT O/N. Solvent was removed and the residue waspurified by FC on silica gel (eluent: from cHex to 30% EtOAc) to afford:(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p26): 791 mg, 69% purity, and(1S,3S/1R,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p27): 653 mg, 87% purity, that were used assuch in the next step. MS (m/z): 328.3 [MH]⁺.

Preparation 34:(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane(TRANS)

(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p32, TRANS, 791 mg, 2.42 mmol) was dissolved in THF (15 mL) and LiAlH₄1M in THF (4.83 mL, 4.83 mmol) was added dropwise at 0° C. The reactionwas refluxed for 1 h, then cooled down to −20° C. and quenched withNa₂SO₄*10 H₂O. The mixture was filtered over a pad of celite washingwith EtOAc, and the solution was concentrated to afford(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane(p34, TRANS, 734 mg) as oil that was used as crude in the next step. MS(m/z): 300.4 [MH]⁺.

Preparation 28:(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (TRANS)

Step a:(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p26, TRANS, 791 mg, 2.42 mmol) was dissolved in THF (15 mL) and LiAlH₄1M in THF (4.83 mL, 4.83 mmol) was added dropwise at 0° C. The reactionwas refluxed for 1 h, then cooled down to −20° C. and quenched withNa₂SO₄*10 H₂O. The mixture was filtered over a pad of celite washingwith EtOAc, and the solution was concentrated to afford(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane(TRANS, 734 mg) as oil that was used as crude in the next step.

Step b:(1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane(TRANS, 734 mg, from step a) was dissolved in DCM (15 mL) and themixture was cooled down to 0° C. ACE-Cl (520 uL, 4.82 mmol) was addedand the mixture was allowed to reach RT and left stirring at thattemperature O/N. The day after solvent was eliminated under reducedpressure and the residue dissolved in MeOH (12 mL). The mixture wasrefluxed for 30 min and then cooled down to RT and concentrated underreduced pressure. Crude material was purified by FC on silica gel(eluent:DCM to DCM/MeOH 9:1) affording(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (p28, TRANS,158 mg, y=31%). MS (m/z): 210.2 [MH]⁺.

Preparation 29:(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (CIS)

The compound was synthesized in analogy to the method described forPreparation 14 starting from(1S,3S/1R,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p27, CIS, 0.653 g, 1.99 mmol) and affording(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (p29, CIS,326 mg, y=78%). MS (m/z): 210.2 [MH]⁺.

Preparation 30 and 31:(1S,3S/1R,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p30) and(1R,3S/1S,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(CIS, p31)

To a solution of [(4-fluorophenyl)methylidene]hydrazine (p5, 0.82 g, 6mmol) in dioxane (10 mL) at 10° C., MnO₂ (4.4 g, 50 mmol) was addedportionwise. The resulting mixture was stirred at RT for 30 min, andthen it was filtered over a pad of Celite washing with dioxane (10 mL)directly into a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione(p10, 1.2 g, 6 mmol) in dioxane (10 mL). The resulting orange/redsolution was left stirring at RT O/N. Solvent was removed and theresidue was purified by FC on silica gel (eluent: cHex to 30% EtOAc) toafford:(1S,3S/1R,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p30): 951 mg, 82% purity and(1R,3S/1S,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p31): 765 mg, 70% purity, that were used assuch in the next step. MS (m/z): 310.3 [MH]⁺.

Preparation 32: (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane(TRANS)

The compound was synthesized in analogy to the method described forPreparation 28 starting from(1S,3S/1R,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p30, 951 mg, 3.07 mmol) and affording(1S,3S/1R,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (p32, TRANS, 257mg, y=44%). MS (m/z): 192.2 [MH]⁺.

Preparation 33: (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane(CIS)

The compound was synthesized in analogy to the method described forPreparation 14 starting from(1R,3S/1S,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-4,6-dionedione (p31, CIS, 765 mg, 2.47 mmol) and affording(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (p33, CIS, 366mg, y=77%). MS (m/z): 192.2 [MH]⁺.

Preparation 34 and 35:(1S,3S/1R,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p34) and(1R,3S/1S,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(CIS, p35)

To a solution of [(3,5-dichlorophenyl)methylidene]hydrazine (p6, 0.85 g,4.49 mmol) in dioxane (10 mL) at 10° C., MnO₂ (3.9 g, 45 mmol) was addedportionwise. The resulting mixture was stirred at RT for 50 min, andthen it was filtered over a pad of Celite washing with dioxane (10 mL)directly into a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione(p10, 0.885 g, 4.4 mmol) in dioxane (5 mL). The resulting orange/redsolution was left stirring at RT O/N. Solvent was removed and theresidue was purified by FC on silica gel (eluent: from cHex to 30%EtOAc) to afford:(1S,3S/1R,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p34): 440 mg, 89% purity and(1R,3S/1S,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p35): 440 mg, 40% purity, that were used assuch in the next step. MS (m/z): 359.9 [MH]⁺.

Preparation 36:(1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (TRANS)

The compound was synthesized in analogy to the method described forPreparation 28 starting from(1S,3S/1R,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p34, TRANS, 440 mg, 1.22 mmol) and affording(1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (p36, TRANS,164 mg, y=55%). MS (m/z): 241.9 [M]⁺.

Preparation 37:(1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (CIS)

The compound was synthesized in analogy to the method described forPreparation 28 starting from(1R,3S/1S,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane-4,6-dione(p35, CIS, 440 mg, 1.22 mmol) and affording(1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (p37, CIS,110 mg, y=27%). MS (m/z): 241.9 [M]⁺.

Preparation 38 and 39:(1R,3S/1S,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, p38) and(1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p39)

To a solution of {[2-(trifluoromethyl)phenyl]methylidene}hydrazine (p7,0.935 g, 4.97 mmol) in dioxane (6 mL) at 10° C., MnO₂ (4.32 g, 49.7mmol) was added portionwise. The resulting mixture was stirred at RT for30 min, then it was filtered over a pad of Celite washing with dioxane(15 mL) directly into a solution of1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 1 g, 4.97 mmol) indioxane (3 mL). The resulting orange/red solution was left stirring atRT O/N. Solvent was removed and the residue was purified by FC on silicagel (eluent: cHex to 30% EtOAc, then to EtOAc 100%) affording a mixtureof both diastereomers that were separated via chiral Prep HPLC

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol + 0.1% isopropylamine) 80/20% v/v Flow rate(ml/min) 18 ml/min DAD detection 220 nm Loop 330 μL Injection 41mg/injection

affording:(1R,3S/1S,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, CIS, p38): 531 mg, 100% purity, r.t. 1.17 min, and(1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, TRANS, p39): 425 mg, 100% purity, r.t. 1.20 min. MS(m/z): 360.0 [MH]⁺.

Preparation 40:(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS)

The compound was synthesized in analogy to the method described forPreparation 13 starting from(1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(p39, TRANS, 128 mg, 0.36 mmol) and affording(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p40,TRANS, 52 mg, y=60%). MS (m/z): 241.9 [M]⁺.

Preparation 41:(1R,3S/1S,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS)

The compound was synthesized in analogy to the method described forPreparation 14 starting from(1S,3R/1R,3S)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(p38, CIS, 529 mg, 1.48 mmol) and affording(1R,3S/1S,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p41,CIS, 181 mg, y=51%). MS (m/z): 241.9 [M]⁺.

Preparation 42, 43, 44 and 45: (1R,3S or1S,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, Enantiomer 1, p42), (1S,3R or1R,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, Enantiomer 2, p43), (1S,3S or1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, Enantiomer 1, p44) and (1R,3R or1S,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, Enantiomer 2, p45)

To a solution of{[4-fluoro-2-(trifluoromethyl)phenyl]methylidene}hydrazine (p8, 1.81 g,8.78 mmol) in dioxane (12 mL) at 10° C., MnO₂ (7.26 g, 83.5 mmol) wasadded portionwise. The resulting mixture was stirred at RT for 30 min,then it was filtered over a pad of Celite washing with dioxane (30 mL)directly into a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione(p10, 1.68 g, 8.35 mmol) in dioxane (6 mL). The resulting orange/redsolution was left stirring at RT O/N. Solvent was removed to obtain anorange gum that was purified by FC on silica gel (eluent from Cy toEtOAc 40%) to obtain a mixture of both racemic diastereomers (2.2 g)that was separated into 4 single enantiomers by chiral Prep HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 80/20% v/v Flowrate (ml/min) 16 ml/min DAD detection 220 nm Loop 1000 μL Injection 44mg/injection

affording: (1R,3S or1S,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, CIS, Enantiomer 1, p42): 500 mg, 98.4% purity, r.t.5.8 min, (1S,3R or1R,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, CIS, Enantiomer 2, p43): 441 mg, 98% purity, r.t.6.6 min, (1S,3S or1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, TRANS, Enantiomer 1, p44): 361 mg, 99% purity, r.t.7.3 min, and (1R,3R or1S,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, TRANS, Enantiomer 2, p45): 403 mg, 100% purity, r.t.9.3 min. MS (m/z): 378.2 [MH]⁺.

Preparation 46: (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1)

Step a: (1S,3S or1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, TRANS, Enantiomer 1, p44, 361 mg, 0.96 mmol) wasdissolved in THF (5 mL) and LiAlH₄ 1M in THF (1.92 mL, 1.92 mmol) wasadded dropwise at 0° C. The resulting orange solution was heated atreflux for 1 h. Then it was cooled down to 0° C. and quenched withNa₂SO₄*10 H₂O until gas evolution ceased. It was filtered over a pad ofCelite washing with EtOAc, the solution was concentrated to afford(1S,3S or1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1, 291 mg) as colourless oil.

Step b: (1S,3S or1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1, 291 mg, from step a) was dissolved in MeOH (10 mL)under N₂ and ammonium formate (523 mg, 8.3 mmol) was added. Then Pd/C(33 mg) was added. The resulting mixture was stirred at reflux for 1 h.After cooling it was filtered over a pad of Celite, the solvent wasevaporated and MeOH and 1.5 mL of HCl ˜1.25M in MeOH was added. Solventwas eliminated under reduced pressure and the residue was loaded on a 5g SCX cartridge washing with MeOH and eluting with NH₃ 1M in MeOH.Solvent was eliminated under reduced pressure to obtain a yellow oilthat was purified by C18 cartridge (eluent from Water+0.1% HCOOH to 25%ACN+0.1% HCOOH) then loaded on a SCX cartridge (washing with MeOH andeluting with NH₃ 1M in MeOH) to obtain (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p46, 42 mg, y=17%) as yellow oil. MS (m/z): 260.2 [M]⁺.

Preparation 47: (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 2)

The compound was synthesized in analogy to the method described forPreparation 46 starting from (1R,3R or1S,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, TRANS, Enantiomer 2, p45, 403 mg, 1.07 mmol) andaffording (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p47, TRANS, Enantiomer 2, 93 mg, y=33%). MS (m/z): 260.2 [M]⁺.

Preparation 48: (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1)

The compound was synthesized in analogy to the method described forPreparation 46 starting from (1R,3S or1S,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, CIS, Enantiomer 1, p42, 500 mg, 1.33 mmol) andaffording (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p48, CIS, Enantiomer 1, 126 mg, y=36%). MS (m/z): 260.2 [M]⁺.

Preparation 49: (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2)

The compound was synthesized in analogy to the method described forPreparation 46 starting from (1S,3R or1R,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, CIS, Enantiomer 2, p43, 441 mg, 1.17 mmol) andaffording (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p49, CIS, Enantiomer 2, 76 mg, y=25%). MS (m/z): 260.2 [M]⁺.

Preparation 50 and 51:(1S,3S/1R,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane-4,6-dione(TRANS, p50) and(1R,3S/1S,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane-4,6-dione(CIS, p51)

To a solution of 5-methanehydrazonoyl-2-(trifluoromethyl)pyridine (p9,0.8 g, 4.22 mmol) in dioxane (15 mL) at 10° C., MnO₂ (3.6 g, 42.2 mmol)was added portionwise. The resulting mixture was stirred at RT for 45min, then it was filtered over a pad of Celite washing with dioxane andthis solution was added to a solution of1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 0.766 g, 3.8 mmol) indioxane (5 mL). The resulting orange solution was left stirring at RTO/N. Solvent was removed and the residue was purified by FC on silicagel (eluent: from cHex to 45% EtOAc) to afford:(1S,3S/1R,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 1, TRANS, p50): 450 mg and(1R,3S/1S,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane-4,6-dione(Diastereoisomer 2, CIS, p51): 360 mg, that were used as such in thenext step. MS (m/z): 361.0 [MH]⁺.

Preparation 52:(1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS)

The compound was synthesized in analogy to the method described forPreparation 14 starting from(1R,3S/1S,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane-4,6-dione(p51, CIS, 0.36 g, 1 mmol) and affording(1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(p52, CIS, 100 mg, y=41%). MS (m/z): 243.3 [M]⁺.

Preparation 53: 4-methyl-1,3-oxazole-5-carboxylic acid

A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 ml, 121.51mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120° C. After 6hrs the mixture was allowed to cool to RT and stirred under nitrogenO/N. The mixture was treated with 3M NaOH (120 mL, reaction moderatelyexothermic) and stirred at RT for 4 hours. EtOAc (120 mL) was added andthe phases allowed separating. The organic layer was discarded while theaqueous was acidified with 37% aqueous HCl to pH 2 (˜40 mL). Aprecipitate started to form. The suspension was treated with EtOAc (160mL) and, vigorously shaken until the precipitate had dissolved. Phaseswere separated and the aqueous one was further extracted with EtOActwice (120 mL). The combined organic layers were concentrated to lowvolume. Fresh EtOAc (160 mL) was added and the mixture evaporated todryness under vacuum. The collected solid was placed in the oven at 45°C. O/N under reduced pressure affording4-methyl-1,3-oxazole-5-carboxylic acid (p53, 8.52 g, y=44%) as rustybrown solid. MS (m/z): 128.0 [MH]⁺.

Preparation 54: 1-methanesulfonyl-1H-1,2,3-benzotriazole

To a solution of benzotriazole (5 g, 42 mmol) and pyridine (5.4 mL, 67.2mmol) in dry toluene (50 mL), MsCl (3.9 mL, 50.36 mmol) in dry toluene(10 mL) was added dropwise at 0° C. under N₂ atmosphere and the mixturewas stirred O/N at RT. The mixture was diluted with ethyl acetate (20mL), washed with water (2×30 mL), brine (30 mL), dried over MgSO₄,filtered and evaporated under vacuum affording1-methanesulfonyl-1H-1,2,3-benzotriazole (p54, 8.44 g, y=quant). NMR: ¹HNMR (Acetone-d₆) δ: 8.21 (dt, 1H), 8.04 (dt, 1H), 7.86-7.75 (m, 1H),7.67-7.57 (m, 1H), 3.76 (s, 3H)

Preparation 55: methyl6-(1H-1,2,3-benzotriazole-1-carbonyl)pyridine-2-carboxylate

A mixture of 6-(methoxycarbonyl)pyridine-2-carboxylic acid (4 g, 22.08mmol), 1-methanesulfonyl-1H-1,2,3-benzotriazole (p54, 4.35 g, 22.08mmol) and triethylamine (6.15 mL, 44.16 mmol) was refluxed in THF (150mL) 4 hrs. The solvent was evaporated and the residue was dissolved inDCM. The organic layer was washed with water, dried, and evaporated togive methyl 6-(1H-1,2,3-benzotriazole-1-carbonyl)pyridine-2-carboxylate(p55, 5.8 g, y=93%). MS (m/z): 283.2 [MH]⁺.

Preparation 56: methyl 6-carbamoylpyridine-2-carboxylate

methyl 6-(1H-1,2,3-benzotriazole-1-carbonyl)pyridine-2-carboxylate (p55,1.9 g, 6.73 mmol) was stirred with ammonium hydroxide (30% aqueoussolution, 40 drops, 43 mmol) in MeOH (8 mL) and THF (15 mL) at RT for 2hrs. After evaporation of solvents in vacuo, 2M NaOH (20 mL) was addedto the residue and the mixture then extracted with EtOAc. The combinedorganic layers were dried. Evaporation of the solvent gave methyl6-carbamoylpyridine-2-carboxylate (p56, 310 mg, y=crude). MS (m/z):181.1 [MH]⁺.

Preparation 57: 6-carbamoylpyridine-2-carboxylic acid

A solution of methyl 6-carbamoylpyridine-2-carboxylate (p56, 0.31 g,1.72 mmol) in THF (5 mL) and water (2 mL) at RT was treated with lithiumhydroxide (0.072 g, 1.72 mmol), stirred for 2 hrs, and concentrated. Theconcentrate was dissolved in water (5 mL) and adjusted to pH 7 with 1NHCl. The aqueous solution was evaporated affording6-carbamoylpyridine-2-carboxylic acid (p57, 550 mg, y=crude). MS (m/z):166.0 [M]⁺.

Preparation 58: methyl 6-(methylcarbamoyl)pyridine-2-carboxylate

methyl 6-(1H-1,2,3-benzotriazole-1-carbonyl)pyridine-2-carboxylate (p55,0.75 g, 2.66 mmol) was stirred with Methylamine 2M in THF (1.33 mL, 2.66mmol) in THF (25 mL) at RT for 4 hrs. After evaporation of solvents invacuum, 2 M NaOH (20 mL) was added to residue and extracted with EtOAc.The combined organic layers were dried. Evaporation of the solvent gavemethyl 6-(methylcarbamoyl)pyridine-2-carboxylate (p58, 350 mg, y=68%).MS (m/z): 195.1 [MH]⁺.

Preparation 59: 6-(methylcarbamoyl)pyridine-2-carboxylic acid

A solution of methyl 6-(methylcarbamoyl)pyridine-2-carboxylate (p58,0.592 g, 3.05 mmol) in THF (7 mL) and water (3 mL) at RT was treatedwith LiOH—H₂O (0.128 g, 3.05 mmol), stirred for 1 h, and concentrated.The concentrate was dissolved in water (5 mL) and adjusted to pH 7 with1N HCl. The aqueous solution was evaporated and the residue was purifiedby C₁₈ cartridge (eluent: from water to 10% CH₃CN) to afford afterevaporation 6-(methylcarbamoyl)pyridine-2-carboxylic acid (p59, 540 mg,y=98%). MS (m/z): 181.1 [MH]⁺.

Preparation 60: methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate

Methyl 6-(1H-1,2,3-benzotriazole-1-carbonyl)pyridine-2-carboxylate (p55,1.5 g, 5.32 mmol) was stirred with Dimethylamine 2M in THF (2.66 mL,5.32 mmol) in THF (35 mL) at RT for 4 hrs. After evaporation of solventsin vacuo, 2M NaOH (20 mL) was added to the residue and extracted withEtOAc. The combined organic layers were dried. Evaporation of thesolvent gave methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate (p60,250 mg, y=22%). MS (m/z): 209.1 [MH]⁺.

Preparation 61: 6-(dimethylcarbamoyl)pyridine-2-carboxylic acid

A solution of methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate (p60,0.36 g, 1.73 mmol) in THF (6 mL) and water (2 mL) at RT was treated withLiOH—H₂O (0.072 g, 1.73 mmol), stirred for 1 h and then concentrated.The concentrate was dissolved in water (5 mL) and adjusted to pH 7 with1N HCl. The aqueous solution was evaporated and the residue was purifiedby FC on C18 cartridge (eluent: water to 10% CH₃CN). After evaporation6-(dimethylcarbamoyl)pyridine-2-carboxylic acid was obtained (p61, 500mg, y=crude). MS (m/z): 195.2 [MH]⁺.

Preparation 62: ethyl 2-(pyridin-3-yl)-1,3-oxazole-4-carboxylate

Ethyl 2-bromo-1,3-oxazole-4-carboxylate (200 mg, 0.9 mmole),3-pyridineboronic acid (144 mg, 1.17 mmole), were combined in a screwcap vial, to this was added 1,4-dioxane (5 mL) and 2M Na₂CO₃ (1.13 mL,2.27 mmol); N₂ was bubbled through the mixture for 1′, and thenPd(PPh₃)₄ (100 mg, 0.09 mmol) was added. The vial was capped then heatedat 100° C. After 2 hrs the mixture was cooled to RT, diluted with EtOAc,filtered through a pad of Celite washing with EtOAc, and concentrated.The crude material was purified by FC on silica cartridge (eluent: fromcHex to EtOAc) to obtain ethyl2-(pyridin-3-yl)-1,3-oxazole-4-carboxylate (p62, 71 mg, y=35%). MS(m/z): 219.1 [MH]⁺.

Preparation 63: ethyl 2-(pyridin-3-yl)-1,3-oxazole-4-carboxylate

Ethyl 2-(pyridin-3-yl)-1,3-oxazole-4-carboxylate (p62, 380 mg, 1.74mmol) was dissolved in THF/water (5 mL/2 mL) and LiOH H₂O (72 mg, 1.74mmol) was added. The mixture was stirred at RT for 2 hrs. Solvent wasremoved in vacuo, the residue was dissoved with water and acidified with6N HCl to pH 4. No precipitation was observed, the solution wasevaporated affording ethyl 2-(pyridin-3-yl)-1,3-oxazole-4-carboxylate(p63, 330 mg, y=crude). MS (m/z): 191.1 [MH]⁺.

Preparation 64: 4-(1,3-oxazol-2-yl)benzoic acid

A solution of 4-carbamoylbenzoic (4.8 g, 29 mmol) and2-bromo-1,1-diethoxyethane (8.7 mL, 58 mmol) in Dioxane (60 mL) wasstirred at reflux (101° C.) for 3.5 hrs. The solids were filtered outand the filtrate was concentrated in vacuo. The residue was purified byreverse phase chromatography on C18 cartridge (eluent: Water+0.1% HCOOHto 30% ACN+0.1% HCOOH) to obtain 4-(1,3-oxazol-2-yl)benzoic acid (p64,232 mg, y=4%). MS (m/z): 190.1 [MH]⁺.

Preparation 65:4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol

To a solution of 4-methyl-1,3-oxazole-5-carboxylic acid (p53, 2 g, 15.7mmol) in DMF (9 mL), 4-Methyl-3-thiosemicarbazide (1.82 g, 17.27 mmol)was added. DIPEA (4.8 mL, 28.26 mmol) was added dropwise at RT, then themixture was cooled with an ice bath before adding T3P (50% w/w in EtOAc)(14 mL, 23.55 mmol). The reaction was stirred at RT O/N. NaOH 4Msolution (15 mL) was added (resulting pH=8). The reaction was dilutedwith EtOAc and the two resulting phases were separated (the upperorganic layer eliminated). Additional 4M NaOH was added up to pH 11 andthe mixture heated to 70° C. for 40 min. The clear rusty red solutionwas then cooled down to RT in 3 hours, then 37% HCl was slowly addedtill pH 5. The clear solution was extracted 3 times with DCM, combinedorganics were dried and concentrated to obtain a brown solid.

Crude material was purified by C18 cartridge (eluting from H₂O+0.1%HCOOH to 20% MeCN+0.1% HCOOH). Fractions containing the product werecollected and concentrated to reduce the volume, then extracted twicewith DCM to obtain4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol (p65,605 mg, y=17%) as yellow solid. MS (m/z): 197.1 [MH]⁺.

Preparation 66: 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole-3-thiol

To a solution of oxane-4-carboxylic acid (5 g, 38.42 mmol) in DMF (23mL), 4-Methyl-3-thiosemicarbazide (4.45 g, 42.26 mmol) was added. DIPEA(11.8 mL, 69.15 mmol) was added dropwise at RT, then the mixture wascooled with an ice bath before adding T3P (50% w/w in EtOAc) (35 mL,57.63 mmol). The reaction was stirred at RT O/N. NaOH 4M solution wasadded (resulting pH=8). The reaction was diluted with EtOAc and the tworesulting phases were separated (the upper organic layer eliminated).Additional 4M NaOH was added up to pH 11 and the mixture heated to 70°C. for 40 min. The solution was then cooled down to RT, then cooled downto 0° C. and HCl 6N was slowly added till pH˜5. The white precipitatewas filtered and washed with cHex, then dried at 50° C. overnight toafford 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole-3-thiol (3.47 g) aswhite solid.

The mother liquor was extracted with DCM (2×), the organic layer wasdried and evaporated to obtain an oil which was triturated with Et₂O toafford an off-white precipitate which was filtered and dried overnightat 50° C. to afford further 1.8 g of title compound4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole-3-thiol (p66, total y=69%) aspale yellow solid. MS (m/z): 200.2 [MH]⁺.

The following intermediates were prepared in analogy with Preparation 66starting from the corresponding carboxylic acids either previouslydescribed or commercially available.

Prep num. Structure Name Yield % MS (m/z) p67

4-methyl-5-{8- oxabicyclo[3.2.1]octan-3-yl}- 4H-1,2,4-triazole-3-thiol93 226.2 p68

5-cyclohexyl-4-methyl-4H- 1,2,4-triazole-3-thiol 70 198.0 p69

4-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)piperidin-2- one 9 213.1p70

1-methyl-4-(4-methyl-5- sulfanyl-4H-1,2,4-triazol-3- yl)piperidin-2-one78 227.1 p71

5-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)piperidin-2- one 63 213.2p72

6-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)-1,2- dihydropyridin-2-one24 209.2 p73

3-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)-1,2- dihydropyridin-2-one33 209.1 p74

5-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)-2,3- dihydropyridin-2-one60 209.1 p75

1-methyl-5-(4-methyl-5- sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydropyridin-2-one 65 223.1 p76

4-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)-1,2- dihydropyridin-2-one45 209.1 p77

1-methyl-4-(4-methyl-5- sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydropyridin-2-one 51 223.1 p78

4-methyl-5-(pyridin-2-yl)- 4H-1,2,4-triazole-3-thiol 83 193.1 p79

4-methyl-5-(pyridin-3-yl)- 4H-1,2,4-triazole-3-thiol 61 193.1 p80

4-methyl-5-(pyridin-4-yl)- 4H-1,2,4-triazole-3-thiol 84 193.1 p81

4-methyl-5-(2-methylpyridin- 3-yl)-4H-1,2,4-triazole-3- thiol 29 207.2p82

4-methyl-5-(6-methylpyridin- 3-yl)-4H-1,2,4-triazole-3- thiol 54 207.2p83

4-methyl-5-(3-methylpyridin- 2-yl)-4H-1,2,4-triazole-3- thiol 78 207.1p84

5-(2,6-dimethylpyridin-3-yl)- 4-methyl-4H-1,2,4-triazole- 3-thiol 49221.2 p85

5-(2-fluoropyridin-3-yl)-4- methyl-4H-1,2,4- triazole-3-thiol 56 211.1p86

4-methyl-5-[2- (trifluoromethyl)pyridin-3-yl]- 4H-1,2,4-triazole-3-thiol35 261.1 p87

5-(2-methoxypyridin-3-yl)-4- methyl-4H-1,2,4-triazole-3- thiol 77 223.2p88

6-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)pyridine-2- carboxamide 27236.2 p89

N-methyl-6-(4-methyl-5- sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide 40 250.1 p90

N,N-dimethyl-6-(4-methyl-5- sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide 39 264.2 p91

4-methyl-5-(pyridazin-4-yl)- 4H-1,2,4-triazole-3-thiol 83 194.1 p92

4-methyl-5-(pyridazin-3-yl)- 4H-1,2,4-triazole-3-thiol 79 194.1 p93

4-methyl-5-(pyrimidin-4-yl)- 4H-1,2,4-triazole-3-thiol 93 194.1 p94

4-methyl-5-(pyrazin-2-yl)- 4H-1,2,4-triazole-3-thiol 92 194.1 p95

4-methyl-5-(6- methylpyrazin-2-yl)-4H- 1,2,4-triazole-3-thiol 75 208.0p96

4-methyl-5-(5- methylpyrazin-2-yl)-4H- 1,2,4-triazole-3-thiol 72 208.0p97

4-methyl-5-(3- methylpyrazin-2-yl)-4H- 1,2,4-triazole-3-thiol 83 208.0p98

4-methyl-5-(1,2-oxazol-5- yl)-4H-1,2,4-triazole-3-thiol 27 182.9 p99

4-methyl-5-(3-methyl-1,2- oxazol-5-yl)-4H-1,2,4- triazole-3-thiol 74197.0 p100

4-methyl-5-(4-methyl-1,3- thiazol-5-yl)-4H-1,2,4- triazole-3-thiol 64212.9 p101

4-methyl-5-(1,3-thiazol-2- yl)-4H-1,2,4-triazole-3-thiol 59 198.9 p102

4-methyl-5-(1-methyl-1H- pyrazol-4-yl)-4H-1,2,4- triazole-3-thiol 45196.0 p103

4-methyl-5-(1-methyl-1H- pyrazol-5-yl)-4H-1,2,4- triazole-3-thiol 64196.1 p104

5-(furan-2-yl)-4-methyl-4H- 1,2,4-triazole-3-thiol 45 181.9 p105

5-(furan-3-yl)-4-methyl-4H- 1,2,4-triazole-3-thiol 34 181.9 p106

4-methyl-5-(thiophen-2-yl)- 4H-1,2,4-triazole-3-thiol 41 197.9 p107

4-methyl-5-(thiophen-3-yl)- 4H-1,2,4-triazole-3-thiol 43 197.9 p108

4-methyl-5-(1-methyl-1H- pyrrol-2-yl)-4H-1,2,4- triazole-3-thiol 8 195.0p109

4-methyl-5-(1,2,3-thiadiazol- 4-yl)-4H-1,2,4-triazole-3- thiol 55 200.1p110

4-methyl-5-(4-methyl-1,2,3- thiadiazol-5-yl)-4H-1,2,4- triazole-3-thiol89 214.1 p111

4-methyl-5-[2-(pyridin-3-yl)- 1,3-oxazol-4-yl]-4H-1,2,4-triazole-3-thiol 60 260.1 p112

4-methyl-5-(6- phenoxypyridin-3-yl)-4H- 1,2,4-triazole-3-thiol 62 285.1p113

4-methyl-5- {[1,2,4]triazolo[4,3-a]pyridin- 8-yl}-4H-1,2,4-triazole-3-thiol 64 233.1 p114

4-methyl-5- {[1,2,4]triazolo[4,3-a]pyridin- 6-yl}-4H-1,2,4-triazole-3-thiol 83 233.1 p115

4-methyl-5- {[1,2,4]triazolo[4,3- a]pyridin-7-yl}-4H-1,2,4-triazole-3-thiol 76 232.9 p116

4-methyl-5-{3-methyl- [1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazole-3- thiol 97 247.1 p117

4-methyl-5-[4-(1H-1,2,3,4- tetrazol-5-yl)phenyl]-4H-1,2,4-triazole-3-thiol 59 260.2 p118

4-methyl-5-[4-(1,3,4- oxadiazol-2-yl)phenyl]-4H- 1,2,4-triazole-3-thiol55 260.1 p119

4-methyl-5-[4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazole- 3-thiol 44 274.2 p120

4-methyl-5-[4-(4H-1,2,4- triazol-4-yl)phenyl]-4H- 1,2,4-triazole-3-thiol55 259.2 p121

4-methyl-5-[4-(1,3-oxazol-2- yl)phenyl]-4H-1,2,4-triazole- 3-thiol 35258.9 p122

4-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)benzamide 77 235.1 p123

4-(4-methyl-5- sulfanyl-4H-1,2,4- triazol-3-yl)benzonitrile Quant. 217.1p124

1-[4-(4-methyl-5-sulfanyl- 4H-1,2,4-triazol-3- yl)phenyl]ethan-1-one 17234.2 p125

4-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)benzene- 1-sulfonamide 37271.1 p126

3-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3- yl)benzamide 71 235.2 p127

2-(4-methyl-5-sulfanyl-4H- 1,2,4-triazol-3-yl)benzamide 21 235.1

Preparation 128:5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

To a stirred solution of 6-cyanopyridine-3-carboxylic acid (230 mg, 1.55mmol) in DMF (0.9 mL), 4-methyl-3-thiosemicarbazide (180 mg, 1.71 mmol)and DIPEA (0.49 mL, 2.79 mmol) were subsequently added. The mixture wascooled to 0° C. then T3P (50% wt/EA) (1.38 mL, 2.33 mmol) was addedportion-wise. The ice-bath was removed and the resulting reactionmixture was stirred O/N at RT. Aqueous 0.5 M NaOH solution was added(resulting pH˜8) and the two resulting phases were separated (the upperorganic layer was eliminated) then the mixture was heated to 75° C. andstirred for 1.5 h. The solution was cooled to RT and 37% HCl was slowlyadded until pH ˜6. The mixture was extracted with DCM, the organic phasewas dried by using a phase separator cartridge and concentrated. Theresidue was treated with water, the mixture was filtered, the whitesolid was washed with water and dried under vacuum at 45° C. O/Naffording5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile(p128, 224 mg, y=66%). MS (m/z): 218.1 [MH]⁺.

Preparation 129:4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

To a stirred solution of 2-cyanopyridine-4-carboxylic acid (1.0 g, 6.75mmol) in DMF (3.9 mL), 4-methyl-3-thiosemicarbazide (0.78 g, 7.43 mmol)and DIPEA (2.1 mL, 12.15 mmol) were subsequently added. The mixture wascooled to 0° C. then T3P (50% wt/EA) (6.0 mL, 10.13 mmol) was addedportion-wise. The ice-bath was removed and the resulting reactionmixture was stirred O/N at RT. Aqueous 0.5 M NaOH solution was added(resulting pH ˜8) and the two resulting phases were separated (the upperorganic layer was eliminated) then the mixture was heated to 75° C. andstirred for 1.5 h. The solution was cooled to RT and 37% HCl was slowlyadded until pH 5. The mixture was stirred for 5 min then was filtered.The solid was washed with water and dried under vacuum at 45° C. O/Naffording a 1:1 mixture of4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile and4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamidederivatives (p129, 0.74 g) that was used as crude in the next step. MS(m/z): 218.1 [MH]⁺.

Preparation 130:5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide

To a solution of 6-cyanopyridine-3-carboxylic acid (0.5 g, 3.35 mmol) inDMF (5 mL), 4-methyl-3-thiosemicarbazide (390 mg, 3.71 mmol) was added;DIPEA (1.1 mL, 6.75 mmol) was added dropwise at RT, then the mixture wascooled in an ice bath before adding T3P (50% w/w in EtOAc) (3 mL, 5.05mmol). The reaction was stirred at RT O/N. NaOH 4M solution was addeduntil the precipitate, formed during the addition, dissolved (resultingpH=8). The reaction was diluted with EtOAc and the two resulting phaseswere separated (the upper organic layer eliminated). Additional 4M NaOHwas added up to pH 11 and the mixture heated to 70° C. for 2.5 hrs. ThenpH was increased to 11 by adding NaOH (pellets) and the reaction wasstirred at 70° C. for 1 h. The solution was cooled to 0° C., then HCl 6Nwas slowly added till pH 5. A precipitate formed that was filtered undervacuum to obtain5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide(p130, 585 mg, y=74%). MS (m/z): 236.1[MH]⁺.

Preparation 131:6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile

To a stirred solution of 5-cyanopyridine-2-carboxylic acid (1.0 g, 6.75mmol) in DMF (3.9 mL), 4-methyl-3-thiosemicarbazide (0.78 g, 7.43 mmol)and DIPEA (2.1 mL, 12.15 mmol) were subsequently added. The mixture wascooled to 0° C. then T3P (50% wt/EA) (6.0 mL, 10.13 mmol) was addedportion-wise. The ice-bath was removed and the resulting reactionmixture was stirred O/N at RT. Aqueous 0.5 M NaOH solution was added(resulting pH-8) and the two resulting phases were separated (the upperorganic layer was eliminated) then the mixture was heated to 70° C. andstirred for 1.5 h. The solution was cooled to RT and 37% HCl was slowlyadded until pH ˜6. The mixture was stirred for 5 min then was filtered.The solid was washed with water and dried under vacuum at 45° C. O/Naffording6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile(p131, 1.47 g y=96%). MS (m/z): 218.1 [MH]⁺.

Preparation 132:6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide

A mixture of6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile(p131, 1.47 g, 6.75 mmol) and crushed KOH (1.14 g, 20.25 mmol) in t-BuOH(90 mL) was heated to 90° C. and stirred for 1.5 h. After allowing themixture to reach RT it was filtered and the yellow solid washed witht-BuOH then dried under vacuum. The solid was taken up with water, thepH was brought to 4-5 by adding 37% HCl then the mixture was filtered,the solid was washed with water and dried under vacuum at 45° C. O/Naffording6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide(p132, 1.39 g, y=88%). MS (m/z): 236.1 [MH]⁺.

Preparation 133:4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide

Step a: Pyrydine-2,4-dicarboxylic acid (2.5 g, 14.95 mmol) was dissolvedin MeOH (9 mL) and Hydrogen chloride ˜1.25 M solution in Methanol (6 mL)was added. The suspension was left stirring at 50° C. for 8 hrs. Themixture was concentrated under reduced pressure affording2-(methoxycarbonyl)pyridine-4-carboxylic acid (2.35 g, crude) as mixtureof mainly mono and partly di-esther that was used as such in the nextstep.

Step b: 2-(methoxycarbonyl)pyridine-4-carboxylic acid (2.35 g from stepa) was dissolved in water (5 mL), treated with NH₄OH 28% aqueoussolution (15 mL) and the solution was left stirring at RT O/N. Solventwas eliminated under reduced pressure affording2-carbamoylpyridine-4-carboxylic acid and4-carbamoylpyridine-2-carboxylic acid (1.27 g) that was used as such inthe next step.

Step c: To a stirred solution of 4-carbamoylpyridine-2-carboxylic acid(1.27 g from step b) in DMF (5 mL), 4-methyl-3-thiosemicarbazide (884mg, 8.4 mmol) and DIPEA (2.4 mL, 13.7 mmol) were subsequently added. Themixture was cooled to 0° C. then T3P (50% wt/EA) (6.82 mL, 11.39 mmol)was added dropwise. The ice-bath was removed and the resulting reactionmixture was stirred at RT O/N.

Aqueous 3M NaOH solution was added (resulting pH-8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 3M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. The precipitate formed wascollected by filtration and washed with water and Cy, then dried underhigh vacuum affording4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p133, 745 mg, y=21%). MS (m/z): 236.1 [MH]⁺.

Preparation 134: 2-(methoxycarbonyl)-3-methylpyridin-N oxide

To a solution of ethyl 2-methyl-3-pyridinecarboxylate (1.86 mL, 12.1mmol) in DCM (50 mL) mCPBA was added (4.18 g, 24.2 mmol) at RT. Thesolution was stirred at RT for 24 hrs. The solution was filtered andconcentrated. The residue was purified by FC on silica (eluent: DCM to15% MeOH) to a solid still containing mCBA that was dissolved with DCMand washed with NaHCO₃, the organic phase was dried and evaporated toafford 2-(methoxycarbonyl)-3-methylpyridin-N oxide (p134, 1.9 g, y=85%).MS (m/z): 168.1 [M]⁺.

Preparation 135: methyl 6-cyano-3-methylpyridine-2-carboxylate

To a solution of 2-(methoxycarbonyl)-3-methylpyridin-N oxide (p134, 1.9g, 11.29 mmol) in DCM (80 mL) TMSCN was added (2.1 mL, 16.93 mmol)followed, after 5 min, by dimethylcarbamyl chloride (1.56 mL, 16.93mmol). The solution was stirred at RT for 48 hrs. Then 10% K₂CO₃ wasslowly added to make the reaction mixture basic. Organic layer wasseparated, dried and evaporated to provide the crude, which was purifiedby FC on silica cartridge (eluent: Cy to 20% EtOAc) to afford methyl6-cyano-3-methylpyridine-2-carboxylate (p135, 370 mg, y=19%). MS (m/z):177.1 [MH]⁺.

Preparation 136: 6-cyano-2-methylpyridine-3-carboxylic acid

A solution of methyl 6-cyano-3-methylpyridine-2-carboxylate (p135, 0.37g, 2.1 mmol) in THF (6 mL) and water (2 mL) at RT was treated withLiOH—H₂O (0.097 g, 2.3 mmol), stirred for 1 h, and concentrated. Theconcentrate was dissolved in water (5 mL) and adjusted to pH 2 with 1NHCl to provide a precipitate. The precipitate was filtered and washedwith cold water, then dried to obtain6-cyano-2-methylpyridine-3-carboxylic acid (p136, 320 mg, y=94%). MS(m/z): 163.0 [MH]⁺.

Preparation 137:5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

To a solution of 6-cyano-2-methylpyridine-3-carboxylic acid (p136, 320mg, 1.97 mmol) in DMF (2 mL), 4-methyl-3-thiosemicarbazide (228 mg,2.117 mmol) was added; DIPEA (0.605 mL, 3.54 mmol) was added dropwise atRT, then the mixture was cooled in an ice bath before adding T3P (50%w/w in EtOAc) (1.76 mL, 2.96 mmol). The reaction was stirred at RT O/N.NaOH 4M solution was added until pH=8. The reaction was diluted withEtOAc and the two resulting phases were separated (the upper organiclayer eliminated). Additional 4M NaOH solution was added up to pH 9 andthe mixture heated to 70° C. for 5 hrs. The solution was then cooled to0° C. and HCl 6N was slowly added till pH 5. A precipitate formed thatwas filtered. The mother liquor was extracted several times with DCM,the organic phase was dried and evaporated to afford an oil. Afteraddition of water (˜2 mL) a precipitate was obtained. It was filteredand combined with the former precipitate to obtain5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile(p137, 160 mg, y=35%). MS (m/z): 232.1 [MH]⁺.

Preparation 138:1-methyl-4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydropyridin-2-one

A mixture of5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile(p137, 0.16 g, 0.69 mmol) and crushed KOH (0.116 mg, 2.06 mmol) int-BuOH (5 mL) was heated to 85° C. and stirred for 1 h. After allowingthe mixture to reach RT solvent was decanted. The yellow solid was takenup with water, the pH was brought to 4-5 by adding 6 N HCl, and aprecipitate was obtained. Then it was filtered, the solid was driedaffording5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide(p138, 120 mg, y=70%). MS (m/z): 250.2 [MH]⁺.

Preparation 139: 2,5-dimethyl pyrazine-2,5-dicarboxylate

Pyrazine-2,5-dicarboxylic acid (900 mg, 5.35 mmol) was dissolved in MeOH(9 mL) and Hydrogen chloride ˜1.25M solution in Methanol (9 mL) wasadded. Then the mixture was heated to 50° C. and stirred at thattemperature for 8 hrs. Then it was left stirring at RT overnight. Theday after 2 mL more of HCl ˜1.25 M in MeOH was added and the mixtureheated to 50° C. and stirred at that temperaure for further 1 h. Themixture was cooled down to RT and concentrated under reduced pressureaffording 2,5-dimethyl pyrazine-2,5-dicarboxylate (p139, 949 mg, y=90%).MS (m/z): 197.1 [MH]⁺.

Preparation 140:5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyrazine-2-carboxamide

Step a: 2,5-dimethyl pyrazine-2,5-dicarboxylate (p139, 949 mg, 4.84mmol) was dissolved in methanol (10 mL) and 1M NaOH (4.84 mL, 4.84 mmol)was slowly added. The resulting suspension was stirred for 1 h at RT,then organic solvent was evaporated and the aqueous residue wasacidified to pH 2 and concentrated affording5-(methoxycarbonyl)pyrazine-2-carboxylic acid (1.23 g) that was used assuch in the next step.

Step b: 5-(methoxycarbonyl)pyrazine-2-carboxylic acid (1.23 g from stepa) was dissolved in water (5 mL) then NH₄OH 28% aqueous solution (10 mL)was added and the solution was left stirring at RT O/N. Solvent wasremoved under reduced pressure affording5-carbamoylpyrazine-2-carboxylic acid (845 mg) that was used as such inthe next step.

Step c: To a stirred solution of 5-carbamoylpyrazine-2-carboxylic acid(845 mg form step b) in DMF (3 mL), 4-methyl-3-thiosemicarbazide (585mg, 5.56 mmol) and DIPEA (1.59 mL, 9.1 mmol) were subsequently added.The mixture was cooled to 0° C. then T3P (50% wt/EA) (4.52 mL, 7.55mmol) was added dropwise. The ice-bath was removed and the resultingreaction mixture was stirred at RT O/N.

Aqueous 3M NaOH solution was added (resulting pH ˜8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 3M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. The product was collected byfiltration washing with water and Cy. Solid was dried under high vacuumaffording5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyrazine-2-carboxamide(p140, 218 mg, y=19%). NMR: ¹H NMR (DMSO-d₆) δ: 9.18-9.26 (m, 2H),8.35-8.44 (m, 1H), 7.92-8.05 (m, 1H), 3.83 (s, 3H)

Preparation 141: 1,5-di-tert-butyl1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate

To a stirred solution of 3H-imidazo[4,5-b]pyridine-5-carboxylic acid(1.0 g, 6.13 mmol), TEA (2.4 mL, 15.33 mmol) and DMAP (0.15 g, 1.23mmol) in DMF (10 mL), Boc₂O (2.94 g, 13.49 mmol) was added portion-wiseand the resulting reaction mixture was stirred O/N at RT. The mixturewas diluted with DCM, washed with saturated ammonium chloride solution,water, dried over sodium sulfate and the solvent removed under reducedpressure. The crude product was purified by FC on silica cartridge(eluting with Cy/EA from 100/0 to 90/10) to give 1,5-di-tert-butyl1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate (p141, 1.37 g, y=85%) aswhite foam. MS (m/z): 320.2 [MH]⁺.

Preparation 142: 1-benzyl 5-tert-butyl1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate

Step a: A stirred solution of1-[(tert-butoxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid(p141, 1.37 g, 5.20 mmol) in MeOH (15 mL) at 0° C. was treated withCs₂CO₃ (0.17 g, 0.52 mmol) and stirred at this temperature for 2 hrs.The reaction mixture was concentrated under reduced pressure and theresidue was taken up with DCM and saturated NH₄Cl solution. The organicphase was dried over sodium sulfate and the solvent removed under vacuumaffording 0.89 g of tert-butyl 1H-imidazo[4,5-b]pyridine-5-carboxylatethat was used as such.

Step b: To a stirred solution of tert-butyl1H-imidazo[4,5-b]pyridine-5-carboxylate (0.89 g from step a) and TEA(0.74 mL, 5.28 mmol) in DCM (10 mL), at 0° C. and under a nitrogenatmosphere, CbzCl (0.61 mL, 4.26 mmol) was added drop-wise. The ice-bathwas removed and the reaction mixture was stirred O/N at RT. The mixturewas diluted with DCM, washed with saturated ammonium chloride solution,water, dried over sodium sulfate and the solvent removed under vacuum.The crude material was purified by FC on silica cartridge (eluting withCy/EA from 100/0 to 35/65) affording 1-benzyl 5-tert-butyl1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate (p142, 0.42 g, y=23%) aswhite foam. MS (m/z): 354.3 [MH]⁺.

Preparation 143:5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazole-3-thiol

Step a: To a stirred solution of 1-benzyl 5-tert-butyl1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate (p142, 0.42 g, 1.19 mmol) inDCM (5 mL), at RT, TFA (1.8 mL) was added and the resulting reactionmixture was stirred at RT for 4 hrs. The mixture was concentrated underreduced pressure and the residue was taken up with DCM. The solution waspassed through a phase separator cartridge and the solution wasconcentrated under vacuum to give1-[(benzyloxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (225mg) as crude product that was used as such in the next step.

Step b: To a stirred solution of1-[(benzyloxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (225mg, from step a) in DMF (0.8 mL), 4-methyl-3-thiosemicarbazide (88 mg,0.83 mmol) and DIPEA (0.24 mL, 1.37 mmol) were subsequently added. Themixture was cooled to 0° C. then T3P (50% wt/EA) (0.68 mL, 1.14 mmol)was added portion-wise. The ice-bath was removed and the resultingreaction mixture was stirred O/N at RT. Aqueous 4M NaOH solution wasadded (resulting pH ˜8) and the two resulting phases were separated (theupper organic layer was eliminated). Further 4M NaOH was added up to pH˜11 then the mixture was heated to 70° C. and stirred for 1.5 h. Thesolution was cooled to RT and 37% HCl was slowly added until pH ˜5. Themixture was stirred for 5 min then was filtered. The solid was washedwith water and dried under vacuum at 45° C. O/N affording5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazole-3-thiol(p143, 125 mg, y=45%) as pale yellow solid. MS (m/z): 233.2 [MH]⁺.

Preparation 144:2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetonitrile

To a stirred solution of 4-(cyanomethyl) benzoic acid (1 g, 6.2 mmol) inDMF (4 mL), 4-methyl-3-thiosemicarbazide (0.72 g, 6.82 mmol) and DIPEA(1.95 mL, 11.16 mmol) were subsequently added. The mixture was cooled to0° C. then T3P (50% wt/EA) (5.36 mL, 9.3 mmol) was added portion-wise.The ice-bath was removed and the resulting reaction mixture was stirredO/N at RT. Aqueous 4M NaOH solution was added (resulting pH ˜8). Thereaction was diluted with EtOAc and the two resulting phases wereseparated (the upper organic layer was eliminated). Additional 4M NaOHwas added up to pH ˜9 then the mixture was heated to 70° C. and stirredfor 6 hrs. Further 4M NaOH was added up to adjust pH ˜9. The solutionwas heated to 70° C. for 4 hrs, then it was cooled to RT and 6N HCl wasslowly added until pH 4 and a precipitate was obtained. The precipitatewas filtered and dried to afford2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetonitrile(p144, 900 mg, y=63%). MS (m/z): 231.2 [MH]⁺.

Preparation 145:2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetamide

A mixture of2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetonitrile(p144, 0.75 g, 3.25 mmol) and crushed KOH (0.55 mg, 9.75 mmol) in t-BuOH(10 mL) was heated to 90° C. and stirred for 3 hrs. After allowing themixture to reach RT solvent was decanted. The yellow solid was taken upwith water, the pH was brought to 4-5 by adding 6 N HCl, and aprecipitate was obtained. It was filtered and dried affording2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetamide (p145,420 mg, y=80%). MS (m/z): 249.1 [MH]⁺.

Preparation 146:3-[(2-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

To a suspension of4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol (p65,300 mg, 1.53 mmol) in a mixture MeOH/Acetone (0.75 mL/1.6 mL) at RT,1-Bromo-2-chloroethane (165 μL, 1.99 mmol) was added followed by K₂CO₃(296 mg, 2.14 mmol) and the mixture was stirred at RT for 4 hrs. Themixture was then partitioned between water and EtOAc and phases wereseparated. Organic one was washed with brine then dried and concentratedunder reduced pressure. Crude material was purified by FC on silica gel(eluting from cHex to EtOAc) affording3-[(2-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p146, 237 mg, y=60%). MS (m/z): 259.1 [MH]⁺.

Preparation 147:(4-chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

To a suspension of4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol (p65,300 mg, 1.53 mmol) in a mixture MeOH/Acetone (0.75 mL/1.6 mL) at RT,1-Bromo-4-chlorobutane (230 μL, 1.99 mmol) was added followed by K₂CO₃(296 mg, 2.14 mmol) and the mixture was stirred at RT 4 hrs. Then it waspartitioned between water and EtOAc and phases were separated. Organicone was washed with brine then dried and concentrated under reducedpressure. Crude material was purified by FC on silica gel (eluting fromcHex to EtOAc) affording(4-chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p147, 270 mg, y=61%). MS (m/z): 287.1 [MH].

Preparation 148:3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

To a suspension of4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol (p65,400 mg, 2.03 mmol) in a mixture MeOH/Acetone (1.3 mL/3.2 mL) at RT,1-Bromo-3-chloropropane (260 μL, 2.64 mmol) was added, followed by K₂CO₃(392 mg, 2.84 mmol) and the mixture was stirred at RT for 4.5 hrs. Itwas partitioned between water and EtOAc and phases were separated.Organic one was washed with brine then dried and concentrated underreduced pressure. Crude material was purified by FC on silica gel(eluting from cHex to EtOAc) affording3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 400 mg, y=65%), as pale yellow solid. MS (m/z): 273.1 [MH]⁺.

The following intermediates were prepared in analogy with Preparation148 reacting the corresponding thiotriazoles, either previouslydescribed or commercially available, with 1-Bromo-3-chloropropane.

Prep. Numb Structure Name Yield % MS (m/z) p149

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(oxan-4-yl)-4H- 1,2,4-triazole63 276.1 p150

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-{8- oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazole 72 302.2 p151

3-[(3- chloropropyl)sulfanyl]-5- cyclohexyl-4-methyl-4H- 1,2,4-triazole88 274.0 p152

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}morpholine 79 277.2 p153

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one 62 289.2 p154

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1-methylpiperidin-2- one 93 303.2 p155

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one 74 289.2 p156

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin- 2-one 80 285.2 p157

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin- 2-one 18 285.2 p158

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin- 2-one 39 285.2 p159

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2- dihydropyridin-2-one 80 299.2 p160

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin- 2-one 36 285.2 p161

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2- dihydropyridin-2-one 80 299.2 p162

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine 80 269.2 p163

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine 88 269.2 p164

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine 83 269.2 p165

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine 63 283.2 p166

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine 67 283.2 p167

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4- triazol-3-yl}-3-methylpyridine 84 282.9 p168

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-2,6-dimethylpyridine 50 297.2 p169

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol- 3-yl}-2-(trifluoromethyl)pyridine 83 337.2 p170

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-2-methoxypyridine 99 299.2 p171

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-2- carbonitrile 30 294.2 p172

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-2- carbonitrile 20 294.1 p173

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-2- carboxamide 31 312.2 p174

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-3- carboxamide 79 312.1 p175

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-2- carboxamide 33 312.1 p176

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-2- carboxamide 41 312.1 p177

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-N-methylpyridine-2- carboxamide 99 326.2 p178

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol- 3-yl}-N,N-dimethylpyridine-2- carboxamide 52 340.2 p179

6-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-5-methylpyridine-2- carboxamide 84 326.2 p180

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl)pyridazine 72 270.2 p181

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridazine 76 270.2 p182

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyrimidine 71 269.9 p183

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyrazine 84 270.1 p184

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-6-methylpyrazine 73 283.9 p185

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-5-methylpyrazine 79 283.9 p186

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-3-methylpyrazine 80 283.9 p187

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyrazine-2- carboxamide  7 313.1 p188

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazole 62 259.0 p189

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4- triazole 80 273.0 p190

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4- triazole 70 289.0 p191

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole 84 274.9 p192

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4- triazole 86 272.0 p193

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(1-methyl-1 H-pyrazol-5-yl)-4H-1,2,4- triazole 87 272.3 p194

3-[(3- chloropropyl)sulfanyl]-5- (furan-2-yl)-4-methyl-4H-1,2,4-triazole 74 257.9 p195

3-[(3- chloropropyl)sulfanyl]-5- (furan-3-yl)-4-methyl-4H-1,2,4-triazole 83 257.9 p196

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(thiophen-2-yl)-4H-1,2,4-triazole 85 273.9 p197

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(thiophen-3-yl)-4H-1,2,4-triazole 77 273.9 p198

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4- triazole 76 271.0 p199

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,2,3-thiadiazole  3 276.1 p200

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-4-methyl-1,2,3- thiadiazole 93 290.16 p201

3-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-1,3- oxazol-2-yl)pyridine 45 336.2 p202

5-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}-2-phenoxypyridine 80 361.2 p203

3-[(3- chloropropyl)sulfanyl]-4- methyl-5- {[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4- triazole 28 309.2 p204

3-[(3- chloropropyl)sulfanyl]-4- methyl-5- {[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4- triazole 77 309.2 p205

3-[(3- chloropropyl)sulfanyl]-4- methyl-5- {[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4- triazole 29 309.1 p206

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-{3-methyl-[1,2,4]triazolo[4,3- a]pyridin-6-yl}-4H-1,2,4- triazole 71 323.2 p207

3-[(3- chloropropyl)sulfanyl]-5- {1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl- 4H-1,2,4-triazole 27 309.1 p208

5-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)-1H-1,2,3,4- tetrazole 52 336.2 p209

2-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)-1,3,4- oxadiazole Quant 336.2 p210

3-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)-5-methyl- 1,2,4-oxadiazole 53 350.2 p211

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H- 1,2,4-triazole 49 335.2 p212

3-[(3- chloropropyl)sulfanyl]-4- methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4- triazole 61 335.2 p213

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}benzamide 55 311.1 p214

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}benzonitrile 93 293.2 p215

1-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)ethan-1-one 59 309.9 p216

4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}benzene-1- sulfonamide 48 347.1 p217

2-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)acetonitrile 65 307.1 p218

2-(4-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}phenyl)acetamide 50 325.2 p219

3-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}benzamide 48 311.2 p220

2-{5-[(3- chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}benzamide 31 311.2

Preparation 221:1-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]ethan-1-one

To a stirred solution of 1-acetylpiperidine-4-carboxylic acid (1 g, 5.84mmol) in DMF (3 mL), 4-methyl-3-thiosemicarbazide (676 mg, 6.4 mmol) andDIPEA (1.83 mL, 10.5 mmol) were subsequently added. The mixture wascooled to 0° C. then T3P (50% wt/EA) (5.21 mL, 8.7 mmol) was addeddropwise. The ice-bath was removed and the resulting reaction mixturewas stirred at RT for 2 hrs.

Aqueous 3M NaOH solution was added (resulting pH ˜8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 3M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. The mixture was extractedwith DCM several times. Aqueous phase was concentrated under reducedpressure and the residue was purified by FC on a C18 cartridge (eluentwater+0.1% HCOOH→50% ACN+0.1% HCOOH) affording1-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]ethan-1-one(p221, 793 mg, y=56%). MS (m/z): 241.2 [MH]⁺.

Preparation 222:1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-1-yl)ethan-1-one

To a suspension of1-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]ethan-1-one(p221, 793 mg, 3.3 mmol) in a mixture MeOH/Acetone (4 mL/9 mL) at RT1-Bromo-3-chloropropane (424 uL, 4.3 mmol) was added followed by K₂CO₃(1.14 g, 8.25 mmol) and the mixture was stirred at RT O/N. Further1-Bromo-3-chloropropane (230 uL, 2.31 mmol) was added followed by K₂CO₃(594 mg, 4.3 mmol) and the mixture was stirred at RT for 2 hrs.

The mixture was partitioned between water and DCM and phases wereseparated. Organic one was washed with brine then dried and concentratedunder reduced pressure. Crude material was purified by FC on silicacartridge (eluent: DCM to DCM/MeOH 9:1) affording1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-1-yl)ethan-1-one(p222, 224 mg, y=21%). MS (m/z): 317.3 [MH]⁺.

Preparation 223: tert-butyl4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

To a stirred solution of 1-Boc-piperidine-4-carboxylic acid (1.0 g, 4.36mmol) in DMF (3 mL), 4-methyl-3-thiosemicarbazide (0.504 g, 4.8 mmol)and DIPEA (1.37 mL, 7.85 mmol) were subsequently added. The mixture wascooled to 0° C. then T3P (50% wt/EA) (3.9 mL, 6.54 mmol) was addeddropwise. The ice-bath was removed and the resulting reaction mixturewas stirred at RT for 3 hrs.

Aqueous 3M NaOH solution was added (resulting pH ˜8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 4M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. The product was extractedwith DCM several times. The organic phase was washed with brine,filtered and evaporated to afford tert-butyl4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate(p223, 1.08 g, y=83%) as white solid. MS (m/z): 299.2 [MH]⁺.

Preparation 224: tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate

To a suspension of tert-butyl4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate(p223, 1.08 g, 3.62 mmol) in a mixture MeOH/Acetone (4 mL/9 mL) at RT1-Bromo-3-chloropropane (465 uL, 4.7 mmol) was added followed by K₂CO₃(700 mg, 5.07 mmol) and the mixture was stirred at RT O/N. Then it waspartitioned between water and DCM and phases were separated. Organic onewas washed with brine then dried and concentrated under reducedpressure. Crude material was purified by FC on NH column (eluent: Cy toCy/AcOEt 1:1) affording tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate(p224, 1.08 g, y=79%). MS (m/z): 375.3 [MH]⁺.

Preparation 225: tert-butyl3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate

To a solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (1g, 4.97 mmol) in DMF (3.5 mL), 4-methyl-3-thiosemicarbazide (0.575 g,5.47 mmol) was added. DIPEA (1.5 mL, 8.95 mmol) was added at RT, thenthe mixture was cooled in an ice-bath before adding T3P (50% w/w inEtOAc) (4.1 mL, 6.958 mmol). The reaction was stirred at RT O/N. NaOH 4Msolution (3 mL) was added (resulting pH=8). The reaction was dilutedwith EtOAc. NaOH 4M sol. (1 mL) was added and the mixture was shakenuntil dissolution. Phases were then separated (the upper organic layereliminated). Additional 4M NaOH was added up to pH 11 (8 mL) and theclear orange solution was heated to 70° C. for 1.5 h. The clear yellowsolution was then cooled to RT, then 37% HCl was slowly added till pH4.5. The milky suspension was extracted with DCM (×4) and combinedorganics were dried and concentrated. To the residue (containing DMF)few drops of water were added and a precipitate formed that was filteredand dried under vacuum to obtain tert-butyl3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate(p225, 1.09 g, y=81%) as white solid. MS (m/z): 271.2 [MH]⁺.

Preparation 226: tert-butyl3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}azetidine-1-carboxylate

To a suspension of tert-butyl3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)azetidine-1-carboxylate(p225, 1.09 g, 4.02 mmol) in a mixture MeOH/Acetone (2.2 mL/5.7 mL) atRT, 1-Bromo-3-chloropropane (437 uL, 4.42 mmol) was added, followed byK₂CO₃ (778 mg, 5.63 mmol) and the mixture was stirred at RT for 5 hrs.The mixture was filtered washing with DCM and the filtrate wasconcentrated in vacuum. The crude was purified by FC on silica cartridge(eluent from Cy to EtOAc, then AcOEt to 20% MeOH) to obtain tert-butyl3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}azetidine-1-carboxylate(p226, 1.05 g, y=72%) as yellow oil. MS (m/z): 347.0 [MH]⁺.

Preparation 227: methyl 4-oxocyclohexane-1-carboxylate

To a solution of 4-oxocyclohexane-1-carboxylic acid (840 mg, 5.91 mmol)in methanol (8 mL) was slowly added thionyl chloride (0.51 mL, 7.09mmol) at RT. The reaction mixture was stirred for 3 hrs thenconcentrated under reduced pressure. The residue was taken up with DCMand aqueous saturated sodium bicarbonate, the organic phase was washedwith water, dried over sodium sulfate and the solvent removed undervacuum to give methyl 4-oxocyclohexane-1-carboxylate (p227, 840 mg) thatwas used as crude in the next step. MS (m/z): 157.1 [MH]⁺.

Preparation 228: methyl 4-(benzylamino)cyclohexane-1-carboxylate

To a solution of methyl 4-oxocyclohexane-1-carboxylate (p227, 0.84 g,5.38 mmol) in 1,2-DCE (20 mL) was added benzylamine (0.62 mL, 5.65 mmol)followed by sodium triacetoxyborohydride (1.71 g, 8.07 mmol)portion-wise and the resulting reaction mixture was stirred O/N at RT.The mixture was diluted with aqueous saturated sodium bicarbonatesolution and DCM. The organic phase was washed with brine, dried oversodium sulfate and the solvent removed under reduced pressure. The crudematerial so obtained was submitted to SCX cartridge purification(eluting with MeOH and 1N NH₃/MeOH) affording methyl4-(benzylamino)cyclohexane-1-carboxylate (p228, 1.05 g) that was used ascrude in the next step. MS (m/z): 248.3 [MH]⁺.

Preparation 229: methyl4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylate

Step a: A mixture of methyl 4-(benzylamino)cyclohexane-1-carboxylate(p228, 1.05 g, 4.25 mmol) and palladium hydroxide on carbon (20 weight%, 0.15 g) in MeOH (25 mL) was hydrogenated at atmospheric pressure for24 hrs at RT. Additional palladium hydroxide on carbon (20 weight %,0.15 g) was added and the reaction mixture was placed again underhydrogen atmosphere. After 24 hrs the reaction mixture was filteredthrough Celite and the filtrate concentrated under reduced pressure togive methyl 4-aminocyclohexane-1-carboxylate (0.61 g).

Step b: To a stirred solution of methyl 4-aminocyclohexane-1-carboxylate(0.61 g from step a) in DCM (5 mL), at RT, a solution of Boc₂O (0.14 g,0.64 mmol) in DCM (0.5 mL) was added portion-wise and the resultingreaction mixture was stirred at RT. The reaction mixture wasconcentrated under vacuum and the crude product was purified by FC onsilica cartridge (eluting with Cy/EA from 100/0 to 90/10) affordingmethyl 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylate (p229,0.24 g, y=22%). MS (m/z): 258.3 [MH]⁺.

Preparation 230: tert-butylN-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)carbamate

Step a: To a stirred solution of methyl4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylate (p229, 236 mg,0.92 mmol) in THF/MeOH/water (2 mL/0.5 mL/0.3 mL), at RT, LiOH (58 mg,1.38 mmol) was added and the reaction mixture was warmed to 50° C. andshaken in a PLS apparatus for 3 hrs. The mixture was concentrated undervacuum, the residue was taken-up with DCM and aqueous 0.1N HCl, theorganic phase was dried and the solvent removed under reduced pressureaffording 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid(225 mg) that was used as crude in the next step.

Step b: To a stirred solution of4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (225 mgfrom step a) in DMF (0.6 mL), 4-methyl-3-thiosemicarbazide (107 mg, 1.02mmol) and DIPEA (0.29 mL, 1.66 mmol) were subsequently added. Themixture was cooled to 0° C. then T3P (50% wt/EA) (0.83 mL, 1.38 mmol)was added portion-wise. The ice-bath was removed and the resultingreaction mixture was stirred O/N at RT. Aqueous 4M NaOH solution wasadded (resulting pH ˜8) and the two resulting phases were separated (theupper organic layer was eliminated). Additional 4M NaOH was added up topH ˜11 then the mixture was heated to 70° C. and stirred for 40 min. Thesolution was cooled to RT and 37% HCl was slowly added until pH ˜5.

The reaction mixture was extracted twice with EA, the organic phase waswashed with water, dried over sodium sulfate and concentrated undervacuum to give tert-butylN-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate(275 mg) that was used as such in the next step.

Step c: To a mixture of tert-butylN-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate(275 mg from step b) and potassium carbonate (158 mg, 1.14 mmol) inMeOH/Acetone (0.6 mL/1.6 mL), 1-bromo-3-chloropropane (0.096 mL, 0.97mmol) was added and the resulting reaction mixture was shaken at RT in aPLS apparatus O/N. The mixture was diluted with EA and filtered, thesolid was washed with EA and the filtrate was concentrated under reducedpressure. The crude material was purified by FC on NH column (elutingwith Cy/EA from 100/0 to 55/45) affording tert-butylN-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)carbamate(p230, 139 mg, y=39%). MS (m/z): 389.3 [MH]⁺.

Preparation 231: 3-(ethoxycarbonyl)-2-methylpyridin-N oxide

To a solution of ethyl 2-methyl-3-pyridinecarboxylate (1.86 mL, 12.1mmol) in DCM (50 mL) mCPBA was added (4.18 g, 24.2 mmol) at RT. Thesolution was stirred at RT for 24 hrs. The solution was filtered andconcentrated. The residue was purified by FC on silica cartridge(eluent: from DCM to 10% MeOH) to afford3-(ethoxycarbonyl)-2-methylpyridin-N oxide (p231, 2.23 g, y=quant). MS(m/z): 183.0 [MH]⁺.

Preparation 232: ethyl 6-cyano-2-methylpyridine-3-carboxylate

To a solution of 3-(ethoxycarbonyl)-2-methylpyridin-N oxide (p231, 2 g,10.92 mmol) in DCM (80 mL) TMSCN was added (2.05 mL, 16.37 mmol)followed, after 5 min, by dimethylcarbamyl chloride (1.5 mL, 16.37mmol). The solution was stirred at RT for 48 hrs. Then 10% K₂CO₃ wasslowly added to make the reaction mixture basic. Organic layer wasseparated, dried and evaporated to provide the crude material, which waspurified by FC on silica cartridge (eluent: Cy to 20% EtOAc) to affordethyl 6-cyano-2-methylpyridine-3-carboxylate (p232, 1.23 g, y=59%). MS(m/z): 191.1 [MH]⁺.

Preparation 233: 6-cyano-2-methylpyridine-3-carboxylic acid

A solution of ethyl 6-cyano-2-methylpyridine-3-carboxylate (p232, 1.37g, 7.2 mmol) in THF (25 mL) and water (10 mL) at RT was treated withLiOH—H₂O (0.453 g, 10.8 mmol), stirred for 2 hrs, and concentrated. Theconcentrate was dissolved in water (10 mL) and adjusted to pH 2 with 1NHCl to provide a precipitate. The precipitate was filtered and washedwith cold water. The mother liquor was extracted several times withEtOAC, the organic solution was dried and evaporated and added to theformer solid to obtain 6-cyano-2-methylpyridine-3-carboxylic acid (p233,1.08 g, y=92%). MS (m/z): 163.0 [MH]⁺.

Preparation 234 and 235:5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide(p234) and5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxylicacid (p235)

To a solution of 6-cyano-2-methylpyridine-3-carboxylic acid (p234, 1.08g, 6.66 mmol) in DMF (5 mL), 4-methyl-3-thiosemicarbazide (770 mg, 7.32mmol) was added DIPEA (2.05 mL, 11.99 mmol) was added dropwise at RT,then the mixture was cooled in an icebath before adding T3P (50% w/w inEtOAc) (5.953 mL, 9.99 mmol). The reaction was stirred at RT O/N. NaOH4M solution was added until pH=8. The reaction was diluited with EtOAcand the two resulting phases were separated (the upper organic layereliminated). Additional 4M NaOH was added up to pH 11 and the mixtureheated to 70° C. for 2.5 hrs. Then pH was increased to 11 by adding NaOH(pellet) and the reaction was stirred at 70° C. for 1 h. The solutionwas then cooled to 0° C., then HCl 6N was slowly added till pH 5. Aprecipitate formed that was filtered under vacuum to obtain a solidcontaining 2 products (87% the carboxylic acid derivative, 12% theprimary amide derivative). It was suspended in a mixture MeOH/Acetone (5mL/10 mL) at RT, 1-Bromo-3-chloropropane (435 uL, 4.4 mmol) was added,followed by K₂CO₃ (1.32 g, 9.6 mmol) and the mixture was stirred at RTO/N. It was partitioned between water and DCM and phases were separated.The amide derivative was extracted in the organic phase, that was driedand concentrated under reduced pressure, and the crude material waspurified by FC on silica cartridge (eluent: from Cy to AcOEt) affording5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide(p234, 37 mg, y=3%). MS (m/z): 326.1 [MH]⁺.

The aqueous phase containing the carboxylic acid derivative was driedaffording5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxylicacid (p235, 1 g, y=crude). MS (m/z): 327.2 [MH]⁺.

Preparation 236:5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide

Step a: 3,5-dimethyl pyridine-3,5-dicarboxylate (500 mg, 2.56 mmol) wasdissolved in methanol (2 mL) and 1M NaOH (2.56 mL, 2.56 mmol) was slowlyadded. The resulting yellow solution was stirred for 15 mins at RT, thenorganic solvent was evaporated and the aqueous residue was acidified topH 2 and extracted with DCM (4×). Material detected in aqueous phase,therefore aqueous and organic phase were combined and concentratedaffording 5-(methoxycarbonyl)pyridine-3-carboxylic acid (561 mg) asyellow solid. Presence of ˜10% of starting material and 10% dicarboxylicacid detected. Used as such in the next step.

Step b: 5-(methoxycarbonyl)pyridine-3-carboxylic acid (561 mg from stepa) was dissolved in 7M NH₃ in MeOH (10 mL, 70 mmol). The resulting paleyellow solution turned to a suspension and it was stirred O/N at RT. Notraces of desired compound detected, therefore solvent was evaporatedunder reduced pressure and the residue was treated with NH₄OH 28%aqueous solution (10 mL) and the solution was left stirring at RT for 3hrs. The mixture was then concentrated under reduced pressure affording5-carbamoylpyridine-3-carboxylic acid (235 mg) that was used as such inthe next step.

Step c: To a stirred solution of 5-carbamoylpyridine-3-carboxylic acid(235 mg from step b) in DMF (1.5 mL), 4-methyl-3-thiosemicarbazide (164mg, 1.56 mmol) and DIPEA (0.444 mL, 2.55 mmol) were subsequently added.The mixture was cooled to 0° C. then T3P (50% wt/EA) (1.26 mL, 2.1 mmol)was added dropwise. The ice-bath was removed and the resulting reactionmixture was stirred at RT O/N.

Aqueous 3M NaOH solution was added (resulting pH ˜8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 3M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. No precipitate observed.Aqueous solution was therefore concentrated under reduced pressureaffording5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide (705mg) used as crude in the next step.

Step d: To a suspension of5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide (705mg) in a mixture MeOH/Acetone (4 mL/9 mL) at RT 1-Bromo-3-chloropropane(182 uL, 1.84 mmol) was added followed by K₂CO₃ (488 mg, 3.53 mmol) andthe mixture was stirred at RT O/N. Then it was partitioned between waterand DCM and phases were separated.

Organic one was washed with brine then dried and concentrated underreduced pressure. Crude material was purified by FC on silica cartridge(eluent:DCM to DCM/MeOH 9:1) affording5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide(p236, 73 mg, y=9%). MS (m/z): 312.2 [MH]⁺.

Preparation 237: methyl 3-[(2,2-dimethoxyethyl)carbamoyl]benzoate

A mixture of 3-(methoxycarbonyl)benzoic acid (500 mg, 2.77 mmol),1-Hydroxybenzotriazole hydrate (397 mg, 2.94 mmol),N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (564 mg,2.94 mmol), and TEA (1.16 mL, 8.31 mmol) in DCM (15 mL) was stirred at0° C. for 10 min, then 2,2-dimethoxyethan-1-amine (0.301 mL, 2.77 mmol)was added and the mixture was left stirring at RT O/N. It was washedwith NaHCO₃ (×1), NH₄Cl (×3) and Brine, organic phase was separated,dried and concentrated under reduced pressure affording methyl3-[(2,2-dimethoxyethyl)carbamoyl]benzoate (p237, 548 mg, y=74%) that wasused as such in the next step. MS (m/z): 268.2 [MH]⁺.

Preparation 238: methyl 3-(1,3-oxazol-2-yl)benzoate

Step a: To a solution of methyl3-[(2,2-dimethoxyethyl)carbamoyl]benzoate (p237, 548 mg, 2.05 mmol) inTHF (4 mL), HCl 6N (1 mL) was added and the mixture was stirred at RTfor 1.5 h. Then the mixture was partitioned between brine and AcOEt andthe organic layer was dried, filtered and concentrated affording methyl3-[(2-oxoethyl)carbamoyl]benzoate (426 mg). Used as such in the nextstep.

Step b: To a solution of PPh₃ (1 g, 3.85 mmol) in DCM (35 mL) at RT,iodine (977 mg, 3.85 mmol) was added followed by a solution of methyl3-[(2-oxoethyl)carbamoyl]benzoate (426 mg from step a) in DCM (4 mL) andthe mixture was stirred at RT for 48 hrs. The mixture was washed withsodium thiosulfate solution and water. Organic layer was then dried andconcentrated under reduced pressure. Crude was purified by FC on silicagel (eluent: Cy to AcOEt) affording methyl 3-(1,3-oxazol-2-yl)benzoate(p238, 137.6 mg, y=33%). MS (m/z): 204.1 [MH]⁺.

Preparation 239:3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole

Step a: methyl 3-(1,3-oxazol-2-yl)benzoate (p238, 137.6 mg, 0.68 mmol)was dissolved in MeOH (2 mL) and 1M NaOH (0.68 mL, 1.08 mmol) was slowlyadded. The resulting yellow solution was stirred for 30 mins at RT, thenorganic solvent was evaporated and the aqueous residue was acidified topH 2 and extracted with DCM. Organic phase was dried and concentratedaffording 3-(1,3-oxazol-2-yl)benzoic acid (148 mg) that was used as suchin the next step.

Step b: To a stirred solution of 3-(1,3-oxazol-2-yl)benzoic acid (148 mgfrom step a) in DMF (0.5 mL), 4-methyl-3-thiosemicarbazide (79 mg, 0.75mmol) and DIPEA (0.213 mL, 1.22 mmol) were subsequently added. Themixture was cooled to 0° C. then T3P (50% wt/EA) (0.61 mL, 1.02 mmol)was added dropwise. The ice-bath was removed and the resulting reactionmixture was stirred at RT O/N.

Aqueous 3M NaOH solution was added (resulting pH ˜8) followed by AcOEtand the two resulting phases were separated (the upper organic layer waseliminated). Additional 3M NaOH was added up to pH 11 then the mixturewas heated to 70° C. and stirred for 40 min. The solution was cooled toRT and 6N HCl was slowly added until pH 5. The precipitate was filteredand washed with water and Cy, then collected and dried under high vacuumaffording4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole-3-thiol (67.6mg).

Step c: To a suspension of4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole-3-thiol (67.6mg from step b) in a mixture MeOH/Acetone (1 mL/2.25 mL) at RT1-Bromo-3-chloropropane (34 uL, 0.34 mmol) was added followed by K₂CO₃(90 mg, 0.65 mmol) and the mixture was stirred at RT O/N. Then it waspartitioned between water and DCM and phases were separated. Organic onewas washed with brine then dried and concentrated under reducedpressure. Crude material was purified by FC on silica gel (eluent: Cy toCy/AcOEt 100%) affording3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole(p239, 44.3 mg, y=19%). MS (m/z): 259.2 [MH]⁺.

Preparation 240:1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propan-2-ol

To a suspension of4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-thiol (p65,100 mg, 0.51 mmol) in a mixture MeOH/Acetone (0.33 mL/0.82 mL) at RT,1-bromo-3-chloropropan-2-ol (64 uL, 0.663 mmol) was added, followed byK₂CO₃ (99 mg, 0.714 mmol) and the mixture was stirred at RT O/N. Themixture was partitioned between water and DCM and phases were separated.Organic one was dried and concentrated under reduced pressure to obtain1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propan-2-ol(p240, 117 mg, y=69%) as yellow solid that was used as such in the nextstep. MS (m/z): 289.1 [MH]⁺.

Preparation 241: oxane-4-carbohydrazide

To a stirred solution of methyl tetrahydro-2H-pyran-4-carboxylate (4 g,27.75 mmol) in MeOH (50 mL) at RT, hydrazine monohydrate (10.8 mL, 222mmol) was added portion-wise and the resulting reaction mixture wasstirred at reflux O/N. The mixture was allowed to reach RT andconcentrated under vacuum affording the title compoundoxane-4-carbohydrazide (p241, 3.9 g, y=98%) as white solid. MS (m/z):145.1 [MH]⁺.

Preparation 242:({[(tert-butoxy)carbonyl]amino}amino)(4-methyl-1,3-oxazol-5-yl)methanone

To a stirred suspension of 4-methyl-1,3-oxazole-5-carboxylic acid (1.0g, 7.87 mmol) in DCM (10 mL), at RT, oxalyl chloride (1.5 mL, 11.81mmol) was added portion-wise followed after 3 min by a catalytic amountof DMF (4 drops) and the resulting reaction mixture was stirred at RTfor 2 hrs; then the clear mixture was concentrated under reducedpressure. The residue was dissolved in DCM (5 mL) and this solution wasadded drop-wise to a stirred solution of tert-butyl carbazate (3.64 g,27.55 mmol) and TEA (4.1 mL, 11.02 mmol) in DCM (10 mL), at 0° C. andunder a nitrogen atmosphere. The resulting reaction mixture was stirredat 0° C. for 3 hrs then it was allowed to reach RT and stirred O/N. Themixture was concentrated under vacuum and the residue was taken up withEA and water. The organic phase was washed with water, saturatedammonium chloride solution, dried over sodium sulfate and the solventremoved under reduced pressure. The crude material was purified by FC onsilica cartridge (eluting with Cy/EA from 100/0 to 40/60) to give({[(tert-butoxy)carbonyl]amino}amino)(4-methyl-1,3-oxazol-5-yl)methanone(p242, 2.45 g, y=quant.) as white waxy solid. MS (m/z): 242.2 [MH]⁺.

Preparation 243: 4-methyl-1,3-oxazole-5-carbohydrazide

To a stirred solution of({[(tert-butoxy)carbonyl]amino}amino)(4-methyl-1,3-oxazol-5-yl)methanone(p242, 1.23 g, 5.1 mmol) in dioxane (5 mL), at RT, 4N/dioxane HCl (26mL, 104 mmol) was added portion-wise and the resulting reaction mixturewas stirred at RT for 3 hrs. The mixture was filtered and the solid wasdried under vacuum O/N then it was loaded on a SCX cartridge (elutingwith MeOH and 2N NH₃/MeOH) affording4-methyl-1,3-oxazole-5-carbohydrazide (p243, 366 mg, y=51%) as lightyellow solid. NMR: ¹H NMR (DMSO-d₆) δ: 9.68 (br. s., 1H), 8.38 (s, 1H),4.47 (br. s., 2H), 2.37 (s, 3H)

Preparation 244: methyl hex-5-enecarboximidate hydrochloride

To a stirred solution of 5-hexenenitrile (2 g, 21.02 mmol) and MeOH(0.96 mL) in Et₂O (20 mL), at 0° C., HCl gas was bubbled for 10 min. Thereaction mixture was concentrated under vacuum and the brown oil wastaken up with Et₂O. The solid was filtered, washed with ether and driedunder vacuum affording methyl hex-5-enecarboximidate hydrochloride(p244, 1.20 g, y=42%) as white solid that was used as such in the nextstep. NMR: ¹H NMR (DMSO-d₆) δ: 11.34-11.86 (m, 1H), 5.68-5.89 (m, 1H),4.93-5.11 (m, 2H), 3.98-4.14 (m, 3H), 2.56-2.69 (m, 2H), 2.00-2.13 (m,2H), 1.62-1.78 (m, 2H)

Preparation 245: N,N′-dimethylhexa-5-enimidamide hydrochloride

To a stirred solution of methyl hex-5-enecarboximidate hydrochloride(p244, 1.29 g, 7.88 mmol) in MeOH (6 mL), at RT, a 33% wt. solution ofMeNH₂ in ethanol (5.9 mL, 47.28 mmol) was added and the resultingreaction mixture was stirred at reflux for 6 hrs and O/N at RT. Themixture was then concentrated under vacuum affording crudeN,N′-dimethylhexa-5-enimidamide hydrochloride (p245, 1.47 g) as palebrown oil that was used as such in the next step. MS (m/z): 141.1 [MH]⁺.

Preparation 246:4-methyl-3-(oxan-4-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole

A suspension of N,N′-dimethylhexa-5-enimidamide hydrochloride (p245,1.47 g, 8.32 mmol), oxane-4-carbohydrazide (p241, 1.20 g, 8.32) andK₂CO₃ (1.15 g, 8.32 mmol) in MeOH (50 mL) was heated to reflux andstirred for 24 hrs. The mixture was then filtered and the organicsolution was concentrated under vacuum. The crude material was purifiedby FC on silica cartridge (eluting from DCM to 10% MeOH) to give twobatches of the title compound4-methyl-3-(oxan-4-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole (p246, batch1: 0.20 g, purity >80% by NMR and batch 2: 0.75 g, purity <70% by NMR).NMR: ¹H NMR (CDCl₃) δ: 5.74-5.91 (m, 1H), 4.94-5.12 (m, 2H), 3.99-4.17(m, 2H), 3.53-3.61 (m, 2H), 3.52 (s, 3H), 2.87-2.96 (m, 1H), 2.70-2.77(m, 2H), 2.05-2.25 (m, 4H), 1.83-2.02 (m, 3H)

Preparation 247: 4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal

A slow stream of O₃ in O₂ was passed through a −78° C. cooled solutionof 4-methyl-3-(oxan-4-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole (p246,203 mg, 0.86 mmol) in DCM (10 mL) until a pale blue color persisted (40min). Excess of O₃ was purged by N₂ bubbling, then a solution of PPh₃(248 mg, 0.946 mmol) in DCM (2 mL) was added. The solution was allowedto reach 25° C. and it was stirred for 2 hrs. The solvent was removed invacuo and the crude material was purified by FC on silica cartridge(eluting from DCM to MeOH), to obtain4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal (p247, 100 mg,60% pure) as colourless oil that was used as such in the next step. NMR:¹H NMR (Acetone-d₆) δ: 9.76 (m, 1H), 3.89-4.03 (m, 2H), 3.58-3.65 (m,3H), 3.44-3.56 (m, 2H), 3.01-3.12 (m, 2H), 2.75 (s, 2H), 2.60-2.66 (m,1H), 2.29-2.39 (m, 1H), 1.76-1.98 (m, 5H)

Preparation 248:4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole

A mixture of N,N′-dimethylhexa-5-enimidamide hydrochloride (p245, 458mg, 2.59 mmol), 4-methyl-1,3-oxazole-5-carbohydrazide (p243, 366 mg,2.59 mmol) and K₂CO₃ (537 mg, 3.89 mmol) in MeOH (20 mL) was refluxedfor 32 hrs. The mixture was then allowed to reach RT, concentrated underreduced pressure and the residue was taken-up with DCM and concentratedaqueous sodium bicarbonate solution. The organic phase was washed withwater, dried over sodium sulphate and the solvent removed under vacuum.The crude material was purified by FC on silica cartridge (eluting withDCM/MeOH from 100/0 to 96/4) then further purified by FC on NH column(eluting with Cy/EA from 100/0 to 65/35) affording4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole(p248, 107 mg, y=18%) as pale yellow waxy solid. MS (m/z): 233.2 [MH]⁺.

Example 1:(1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E1)

(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 23 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p146, 25 mg, 0.096 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) were dissolved in DMF (0.2 mL) and heated at 60° C. O/N. Themixture was diluted with water and EtOAc and extracted several timeswith EtOAc. The organic phase was washed with brine, dried andevaporated. The residue was purified by FC on silica gel (eluting fromDCM to 5% of MeOH) to afford(1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E1, 23 mg, y=51%) as yellow foam. NMR: ¹H NMR (Acetone-d₆) δ: 8.27 (s,1H), 7.62 (d, 2H), 7.34 (d, 2H), 3.81 (s, 2H), 3.39 (m, 2H), 2.87 (m,2H), 2.75-2.83 (m, 3H), 2.61-2.73 (m, 3H), 2.43 (s, 2H), 2.21-2.29 (m,1H), 1.61-1.70 (m, 1H), 1.44 (s, 1H), 1.26 (m, 1H), 1.17-1.23 (m, 1H).MS (m/z): 464.3 [MH]⁺.

Example 2 and Example 3: (1R,3R or1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E2, Enantiomer 1) and (1S,3S or1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E3, Enantiomer 2)

(1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E1, 23 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5 μm Mobile phase n-Hexane/Ethanol55/45% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 750 μLInjection 10 mg/injection

Each enantiomer was treated with 1N HCl in Et₂O (1.1 eq) and evaporatedaffording (1R,3R or1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E2, 5.2 mg), Enantiomer 1: ret. time 11.7 min, 100% ee,MS (m/z): 464.3 [MH]⁺, and (1S,3S or1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl)}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E3, 6 mg), Enantiomer 2: ret. time 13.1 min, 97.2% ee, MS(m/z): 464.3 [MH]⁺.

Example 4:(1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E4)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.195 mmol),3-[(3-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p146, 57 mg, 0.22 mmol), Na₂CO₃ (23 mg, 0.22 mmol) and NaI (33 mg, 0.22mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E4, 20.5 mg, y=22%) as pale yellow foam. NMR: ¹H NMR (CDCl₃) δ: 7.95(s, 1H), 7.54 (d, 2H), 7.14-7.23 (m, 2H), 3.68 (s, 3H), 3.28-3.44 (m,2H), 2.85 (s, 3H), 2.68-2.76 (m, 1H), 2.51-2.57 (m, 3H), 2.43-2.50 (m,1H), 2.19-2.25 (m, 1H), 2.11-2.18 (m, 1H), 1.94-2.05 (m, 2H), 1.15-1.24(m, 2H). MS (m/z): 464.3 [MH]⁺.

Example 5:(1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, E5)

(1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E4, 20.5 mg) was dissolved in Et₂O and treated with 1.1 eq of 1N HCl inEt₂O affording, after evaporation,(1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (ES, 22.5 mg) as off-white solid. MS (m/z): 464.3 [MH]⁺.

Example 6:(1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E6)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.2 mmol),(4-chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p147, 63 mg, 0.22 mmol), Na₂CO₃ (23 mg, 0.22 mmol) and NaI (33 mg, 0.22mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E6, 14.5 mg, y=15%) as pale yellow foam. NMR: ¹H NMR (CDCl₃) δ: 7.95(s, 1H), 7.55 (d, 2H), 7.22 (d, 2H), 3.65-3.74 (m, 3H), 3.20-3.33 (m,2H), 2.94 (br. s., 1H), 2.70 (br. s., 1H), 2.54 (s, 6H), 2.14-2.27 (m,2H), 2.05 (d, 2H), 1.82 (m, 3H), 1.19-1.32 (m, 3H). MS (m/z): 492.3[MH]⁺.

Example 7:(1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, E7)

(1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E6, 14.5 mg) was dissolved in Et₂O and treated with 1.1 eq of 1N HCl inEt₂O affording, after evaporation,(1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E7, 13.5 mg) as white solid. MS (m/z): 492.3 [MH]⁺.

Example 8:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E8)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 47 mg, 0.195 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 58 mg, 0.21 mmol), Na₂CO₃ (22 mg, 0.21 mmol) and NaI (31 mg, 0.21mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E8, 35 mg, y=37%) as pale yellow foam. NMR: ¹H NMR (CDCl₃) δ:7.95 (s, 1H), 7.54 (d, 2H), 7.23 (br. s., 2H), 3.73 (s, 3H), 3.37 (m,2H), 2.59-2.94 (m, 5H), 2.55 (s, 3H), 1.97-2.31 (m, 3H), 1.63 (br. s.,4H), 1.25-1.36 (m, 1H), 1.11-1.19 (m, 1H) MS (m/z): 478.3 [MH]⁺.

Example 9 and Example 10: (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E9, Enantiomer 1) and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E10, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS) (E8, 31 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/Ethanol50/50% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 875 μLInjection 15.5 mg/injection

Each enantiomer was treated with 1N HCl in Et₂O (1.2 eq) and evaporatedaffording (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E9, 8.3 mg), Enantiomer 1: ret. time 8.5 min, 100% ee, MS(m/z): 478.3 [MH]⁺, and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E10, 12.9 mg), Enantiomer 2: ret. time 10.9 min, 100% ee,MS (m/z): 478.3 [MH]⁺.

Example 11:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Ell)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 47 mg, 0.195 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 58 mg, 0.21 mmol), Na₂CO₃ (22 mg, 0.21 mmol) and NaI (31 mg, 0.21mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS) (E11, 29 mg, y=31%) as yellow oil. NMR: ¹H NMR (Acetone-d₆) δ:8.28 (s, 1H), 7.63 (d, 2H), 7.40 (d, 2H), 3.77 (s, 3H), 3.16-3.36 (m,2H), 2.46-2.69 (m, 5H), 2.44 (s, 3H), 2.22-2.30 (m, 1H), 1.79-2.03 (m,5H), 1.26-1.35 (m, 1H), 1.19-1.26 (m, 1H), MS (m/z): 478.3 [MH]⁺.

Example 12 and Example 13:(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E12, Enantiomer 1) and(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E13, Enantiomer 2)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS) (E11, 26 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/Ethanol50/50% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 750 μLInjection 13 mg/injection

Each enantiomer was treated with 1N HCl in Et₂O (1.1 eq) and evaporatedaffording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E12, 3.1 mg), Enantiomer 1: ret. time 7.3 min, 100% ee,MS (m/z): 478.3 [MH]⁺, and(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E13, 4.5 mg), Enantiomer 2: ret. time 9.7 min, 100% ee,MS (m/z): 478.3 [MH]⁺.

Example 14:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(TRANS, E14)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-phenyl-5-azaspiro[2.4]heptane (TRANS, p18, 77 mg, 0.44mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 120 mg, 0.44 mmol), Na₂CO₃ (56 mg, 0.53 mmol) and NaI (79 mg,0.53 mmol) in DMF (0.360 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(TRANS, E14, 20.5 mg, y=11%). NMR: ¹H NMR (Acetone-d₆) δ: 8.26 (s, 1H)7.09-7.33 (m, 5H), 3.78 (s, 3H), 3.27-3.36 (m, 2H), 2.47-2.76 (m, 6H),2.41 (s, 3H), 2.09-2.15 (m, 1H), 1.87-2.00 (m, 2H), 1.37-1.65 (m, 2H),1.04-1.17 (m, 2H), MS (m/z): 410.3 [MH]⁺.

Example 15 and Example 16: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E15, Enantiomer 1) and (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E16, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(TRANS) (E14, 15 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% ipa) 25/75% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nmLoop 750 μL Injection 7 mg/injection

affording (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E15, 5 mg), Enantiomer 1: ret. time 10.5 min, MS (m/z): 410.4 [MH]⁺ and(1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E16, 5 mg), Enantiomer 2: ret. time 12.1 min, MS (m/z): 410.4 [MH]⁺.

Example 17:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E17)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS, p19, 42 mg, 0.24mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 65 mg, 0.24 mmol), Na₂CO₃ (31 mg, 0.29 mmol) and NaI (43 mg, 0.29mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E17, 22.5 mg, y=23%). NMR: ¹H NMR (Acetone-d₆) δ: 8.26 (s, 1H)7.09-7.33 (m, 5H) 3.78 (s, 3H) 3.27-3.36 (m, 2H) 2.47-2.76 (m, 6H) 2.41(s, 3H) 2.09-2.15 (m, 1H) 1.87-2.00 (m, 2H) 1.37-1.65 (m, 2H) 1.04-1.17(m, 2H), MS (m/z): 410.3 [MH]⁺.

Example 18 and Example 19:(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E18, Enantiomer 1) and(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E19, Enantiomer 2)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS) (E17, 17 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% ipa) 55/45% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nmLoop 750 μL Injection 8.5 mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E18, 6.6 mg), Enantiomer 1: ret. time 7.9 min, 100% ee, MS (m/z): 410.3[MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E19, 6.6 mg), Enantiomer 2: ret. time 9.3 min, 95.8% ee, MS (m/z):410.3 [MH]⁺.

Example 20:(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptanehydrochloride (E20, Enantiomer 2)

(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(Enantiomer 2, E19, 27 mg) was treated with 1.1 eq of HCl in Et₂Oaffording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, E20, 29 mg), MS (m/z): 410.4 [MH]⁺.

Example 21:(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E21)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p22, 50 mg, 0.193 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 58 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E21, 59 mg, y=62%). NMR: ¹H NMR (Acetone-d₆) δ: 8.27 (s, 1H),7.49 (m, 2H), 7.29-7.37 (m, 1H), 3.80 (s, 3H), 3.32-3.38 (m, 2H),2.47-3.12 (m, 6H), 2.42 (s, 3H), 2.35 (m, 1H), 1.69 (br. s., 1H), 1.42(br. s., 1H), 1.28-1.39 (m, 3H), MS (m/z): 496.3 [MH]⁺.

Example 22 and Example 23: (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E22, TRANS, Enantiomer 1) and (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E23, TRANS, Enantiomer 2)

(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS) (E21, 57 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% ipa) 55/45% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nmLoop 500 μL Injection 11 mg/injection

affording (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E22, 19.4 mg), Enantiomer 1: ret. time 7.7 min, 100% ee, MS (m/z):496.3 [MH]⁺ and (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E23, 19.7 mg) Enantiomer 2: ret. time 9.3 min, 98.6% ee, MS (m/z):496.3 [MH]⁺.

Example 24: (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E24, TRANS, Enantiomer 1)

(1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(Enantiomer 1, E22, 19.4 mg) was treated with 1.1 eq of HCl in Et₂Oaffording (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, E24, 18 mg). MS (m/z): 496.3 [MH]⁺.

Example 25: (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E25, TRANS, Enantiomer 2)

(1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(Enantiomer 2, E23, 19.4 mg) was treated with 1.1 eq of HCl in Et₂Oaffording (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, E25, 18 mg). MS (m/z): 496.3 [MH]⁺.

Example 26:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E26)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.193 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 58 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E26, 39 mg, y=41%). NMR: ¹H NMR (Acetone-d₆) δ: 8.27 (s, 1H), 7.49(d, 2H), 7.38 (s, 1H), 3.76 (s, 3H), 3.20-3.35 (m, 2H), 2.87-3.19 (m,3H), 2.42 (s, 3H), 2.33-2.39 (m, 1H), 2.10-2.19 (m, 1H), 1.92-2.02 (m,2H), 1.42-1.50 (m, 1H), 1.27-1.36 (m, 2H), MS (m/z): 496.3 [MH]⁺.

Example 27 and Example 28:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E27, CIS, Enantiomer 1) and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E28, CIS, Enantiomer 2)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E26, 37 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% ipa) 70/30% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nmLoop 500 μL Injection 9 mg/injection

affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E27, 14 mg) Enantiomer 1: ret. time 7.6 min, 100% ee, MS (m/z):496.3 [MH]⁺ and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E28, 13.8 mg) Enantiomer 2: ret. time 8.8 min, 94.6% ee, MS (m/z):496.3 [MH]⁺.

Example 29:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E29, CIS, Enantiomer 1)

(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E27, 14 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, CIS, E29, 11 mg). MS (m/z): 496.3[MH]⁺.

Example 30:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E30, CIS, Enantiomer 2)

(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E28, 13.8 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, CIS, E30, 11 mg). MS (m/z): 496.3[MH]⁺.

Example 31:(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E31)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (TRANS, p28,0.24 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 71 mg, 0.26 mmol), Na₂CO₃ (31 mg, 0.29 mmol) and NaI (43 mg, 0.29mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E31, 45 mg, y=42%). NMR: ¹H NMR (Acetone-d₆) δ: 8.26-8.29 (m,1H), 7.06-7.17 (m, 1H), 6.93-7.05 (m, 2H), 3.81 (s, 3H), 3.33 (s, 2H),2.52-2.74 (m, 6H), 2.44 (s, 3H), 2.12-2.19 (m, 1H), 1.93-2.02 (m, 2H),1.54 (d, 1H), 1.29-1.40 (m, 1H), 1.17-1.24 (m, 1H), 1.11-1.16 (m, 1H).MS (m/z): 446.4 [MH]⁺.

Example 32 and Example 33: (1R,3S or1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E32, TRANS, Enantiomer 1) and (1S,3R or1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E33, TRANS, Enantiomer 2)

(1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E31, 45 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Mobile phase (Methanol + 0.1%isopropylamine) 18% Flow rate (ml/min) 45 ml/min DAD detection 220 nmLoop 700 μL Injection 15.1 mg/injection

affording (1R,3S or1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E32, 10.8 mg) Enantiomer 1: ret. time 11.5 min, 100% ee, MS(m/z): 446.4 [MH]⁺ and (1S,3R or1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E33, 14.6 mg) Enantiomer 2: ret. time 15.5 min, 100% ee, MS(m/z): 446.4 [MH]⁺.

Example 34: (1R,3S or1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E34, TRANS, Enantiomer 1)

(1R,3S or1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E32, 10.8 mg) was treated with 1.1 eq of HCl in Et₂O affording(1R,3S or1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E34, 11 mg). MS (m/z): 446.5[MH]⁺.

Example 35: (1S,3R or1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E35, TRANS, Enantiomer 2)

(1S,3R or1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E33, 14.6 mg) was treated with 1.1 eq of HCl in Et₂O affording(1S,3R or1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 2, E35, 14.6 mg). MS (m/z): 446.5[MH]⁺.

Example 36:(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E36)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (CIS, p29,50 mg, 0.24 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 71 mg, 0.26 mmol), Na₂CO₃ (31 mg, 0.29 mmol) and NaI (43 mg, 0.29mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E36, 52 mg, y=49%). NMR: ¹H NMR (Acetone-d₆) δ: 8.28 (s, 1H),7.09-7.19 (m, 1H), 6.88-7.04 (m, 2H), 3.77 (s, 5H), 3.19-3.31 (m, 2H),2.73-2.78 (m, 1H), 2.57-2.65 (m, 1H), 2.46-2.55 (m, 2H), 2.43 (s, 3H),2.34-2.39 (m, 1H), 2.09-2.14 (m, 1H), 1.93-2.01 (m, 3H), 1.84 (m, 2H),1.18-1.25 (m, 1H), 1.11-1.16 (m, 1H), MS (m/z): 446.4 [MH]⁺.

Example 37 and Example 38:(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E37, CIS, Enantiomer 1) and(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E38, CIS, Enantiomer 2)

(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS) (E36, 50 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Mobile phase (Methanol + 0.1%isopropylamine) 12% Flow rate (ml/min) 45 ml/min DAD detection 220 nmLoop 700 μL Injection 17.5 mg/injection

affording(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E37, 14.4 mg), Enantiomer 1: ret. time 14.1 min, 100% ee, MS (m/z):446.4 [MH]⁺ and(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E38, 17.1 mg) Enantiomer 2: ret. time 18.5 min, 98.8% ee, MS (m/z):446.4 [MH]⁺.

Example 39:(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E39, CIS, Enantiomer 2)

(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E38, 17.1 mg) was treated with 1.1 eq of HCl in Et₂O affording(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E39, 18 mg). MS (m/z): 446.4[MH]⁺.

Example 40:(1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E40)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (TRANS, p32, 50mg, 0.26 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 79 mg, 0.29 mmol), Na₂CO₃ (31 mg, 0.29 mmol) and NaI (43 mg, 0.29mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E40, 42 mg, y=38%). NMR: ¹H NMR (Acetone-d₆) δ: 8.25-8.31 (m,1H), 7.11-7.21 (m, 2H), 7.00-7.11 (m, 2H), 3.80 (s, 3H), 3.29-3.37 (m,2H), 2.66-2.75 (m, 1H), 2.50-2.66 (m, 5H), 2.44 (s, 3H), 2.10-2.17 (m,1H), 1.90-2.02 (m, 2H), 1.48-1.63 (m, 1H), 1.35-1.47 (m, 1H), 1.11-1.19(m, 1H), 1.04-1.08 (m, 1H) MS (m/z): 428.4 [MH]⁺.

Example 41 and Example 42: (1R,3R or1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E41, TRANS, Enantiomer 1) and (1S,3S or1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E42, TRANS, Enantiomer 2)

(1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E40, 40 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 20% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 700 μL Injection 14mg/injection

affording (1R,3R or1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E41, 14.5 mg), Enantiomer 1: ret. time 11.7 min, 100% ee, MS(m/z): 428.4 [MH]⁺ and (1S,3S or1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E42, 14 mg), Enantiomer 2: ret. time 16.3 min, 100% ee, MS(m/z): 428.5 [MH]⁺.

Example 43: (1R,3R or1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E43, TRANS, Enantiomer 1)

(1R,3R or1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E41, 14.5 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3R or1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E43, 14.7 mg). MS (m/z): 428.5[MH]⁺.

Example 44: (1S,3S or1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (TRANS, E44, Enantiomer 2)

(1S,3S or1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E42, 14 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S or1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 2, E44, 14.3 mg). MS (m/z): 428.5[MH]⁺.

Example 45:(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E45)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (CIS, p33, 50mg, 0.26 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 79 mg, 0.29 mmol), Na₂CO₃ (31 mg, 0.29 mmol) and NaI (43 mg, 0.29mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E45, 52 mg, y=46%). NMR: ¹H NMR (Acetone-d₆) δ: 8.26-8.30 (m, 1H),7.16-7.21 (m, 2H), 7.00-7.08 (m, 2H), 3.77 (s, 3H), 3.15-3.31 (m, 2H),2.62-2.75 (m, 2H), 2.50 (m, 2H), 2.43 (s, 3H), 2.37 (d, 1H), 2.09-2.13(m, 2H), 1.89-1.99 (m, 2H), 1.79-1.88 (m, 2H), 1.06-1.14 (m, 2H), MS(m/z): 428.4 [MH]⁺.

Example 46 and Example 47:(1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E46, CIS, Enantiomer 1) and(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E47, CIS, Enantiomer 2)

(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E45, 50 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 17% Flow rate (ml/min) 46 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 700 μL Injection 17.5mg/injection

affording(1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E46, 17.9 mg), Enantiomer 1: ret. time 12.1 min, 100% ee, MS (m/z):428.4 [MH]⁺ and(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E47, 18.6 mg) Enantiomer 2: ret. time 15.0 min, 100% ee, MS (m/z):428.4 [MH]⁺.

Example 48:(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E48, CIS, Enantiomer 2)

(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E47, 18.6 mg) was treated with 1.1 eq of HCl in Et₂O affording(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E48, 20 mg). MS (m/z): 428.5[MH]⁺.

Example 49:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E49)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p40, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 36 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.13 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanethat was dissolved in Et₂O and DCM and salified with 1.2 eq of HCl 1M inEt₂O to obtain(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E49, 9 mg, y=13%). NMR: ¹H NMR (DMSO-d₆) δ:10.13-10.56 (m, 1H), 8.58 (s, 1H), 7.74-7.80 (m, 1H), 7.60-7.68 (m, 1H),7.43-7.52 (m, 1H), 7.36 (d, 1H), 3.71 (s, 3H), 3.49-3.68 (m, 2H), 3.28(m, 4H), 3.12-3.22 (m, 1H), 2.93-3.07 (m, 1H), 2.48 (br. s., 2H), 2.39(s, 3H), 2.10 (br. s., 2H), 1.52-1.72 (m, 2H), 1.32-1.50 (m, 2H). MS(m/z): 478.4 [MH]⁺.

Example 50 and Example 51: (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E50, TRANS, Enantiomer 1) and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E51, TRANS, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, 55 mg) prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p40, 50 mg, 0.21 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 63 mg, 0.23 mmol), Na₂CO₃ (27 mg, 0.25 mmol) and NaI (38 mg, 0.25mmol) in DMF (0.2 mL) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 70/30% v/v Flow rate (ml/min) 16 ml/min DADdetection 220 nm Loop 500 μL Injection 7 mg/injection

affording (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E50, 17.7 mg) Enantiomer 1: ret. time 7.2 min, 100% ee, MS(m/z): 478.4 [MH]⁺ and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E51, 19.4 mg) Enantiomer 2: ret. time 8.4 min, 95.5% ee, MS(m/z): 478.5 [MH]⁺.

Example 52: (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E52, TRANS, Enantiomer 1)

(1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E50, 17.7 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E52, 17.5 mg). MS (m/z): 478.4[MH]⁺.

Example 53: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E53, Enantiomer 2)

(1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E51, 19.4 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 2, E53, 13 mg). MS (m/z): 478.4[MH]⁺.

Example 54:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E54)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p41, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 36 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.13 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E54, 26 mg, y=45%). NMR: ¹H NMR (Acetone-d₆) δ: 8.29 (s, 1H),7.71-7.78 (m, 1H), 7.54-7.62 (m, 1H), 7.38-7.47 (m, 1H), 7.27-7.33 (m,1H), 3.77 (s, 3H), 3.17-3.37 (m, 3H), 2.83-3.06 (m, 2H), 2.60 (br. s.,4H), 2.44 (s, 3H), 2.41 (br. s., 1H), 1.80-2.02 (m, 4H), 1.51-1.60 (m,1H), 1.14-1.25 (m, 1H), MS (m/z): 478.4 [MH]⁺.

Example 55: (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (CIS, E55, Enantiomer 1)

The compound was prepared as in Example 1, reacting (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p48, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 29 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.11 mL) affording (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, 30 mg, 0.06 mmol) that was dissolved in Et₂O and DCM and salifiedwith 1.2 eq of HCl 1M in Et₂O to obtain (1R,3S or1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E55, 30 mg, y=58%) as yellow solid.NMR: ¹H NMR (DMSO-d₆) δ: 10.12 (br. s., 1H), 8.57 (s, 1H), 7.66 (d, 1H),7.49 (m., 1H), 7.33-7.42 (m, 1H), 3.72-3.84 (m, 1H), 3.61-3.69 (m, 3H),3.39-3.25 (m, 6H), 2.84-3.00 (m, 1H), 2.52-2.62 (m, 2H), 2.37 (s, 3H),1.91-2.27 (m, 4H), 1.61-1.75 (m, 1H), 1.22-1.42 (m, 1H), MS (m/z): 496.4[MH]⁺.

Example 56: (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (CIS, E56, Enantiomer 2)

The compound was prepared as in Example 1, reacting (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, p49, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 29 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.11 mL) affording (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, 29 mg, 0.06 mmol) that was dissolved in Et₂O and DCM and salifiedwith 1.2 eq of HCl 1M in Et₂O to obtain (1S,3R or1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 2, E56, 30 mg, y=58%) as yellow solid.NMR: ¹H NMR (DMSO-d₆) δ: 9.84-10.29 (m, 1H), 8.57 (s, 1H), 7.66 (d, 1H),7.44-7.54 (m, 1H), 7.32-7.42 (m, 1H), 3.71-3.82 (m, 1H), 3.61-3.70 (m,3H), 3.04-3.24 (m, 6H), 2.85-2.99 (m, 1H), 2.52-2.62 (m, 2H), 2.37 (s,3H), 2.11-2.01 (m, 4H), 1.61-1.74 (m, 1H), 1.26 (m, 1H), MS (m/z): 496.4[MH]⁺.

Example 57: (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (TRANS, E57, Enantiomer 1)

The compound was prepared as in Example 1, reacting (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1, p46, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 29 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.11 mL) affording (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E1, 24 mg, 0.048 mmol) that was dissolved in Et₂O and DCM andsalified with 1.2 eq of HCl 1M in Et₂O to obtain (1S,3S or1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (TRANS, Enantiomer 1, E57, 24 mg, y=47%) as yellow solid.NMR: ¹H NMR (DMSO-d₆) δ: 9.93-10.30 (m, 1H), 8.57 (s, 1H), 7.61-7.70 (m,1H), 7.46-7.55 (m, 1H), 7.36-7.44 (m, 1H), 3.69 (s, 4H), 3.48-3.62 (m,2H), 3.34-3.39 (m, 1H), 3.27 (d, 3H), 3.10-3.22 (m, 1H), 2.94-3.08 (m,1H), 2.41-2.47 (m, 1H), 2.38 (s, 3H), 2.09 (br. s., 2H), 1.51-1.70 (m,2H), 1.39-1.49 (m, 1H), 1.30-1.39 (m, 1H), MS (m/z): 496.4 [MH]⁺.

Example 58: (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (TRANS, E58, Enantiomer 2)

The compound was prepared as in Example 1, reacting (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 2, p47, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 29 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.11 mL) affording (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E2, 29 mg, 0.006 mmol) that was dissolved in Et₂O and DCM andsalified with 1.2 eq of HCl 1M in Et₂O to obtain (1R,3R or1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (TRANS, Enantiomer 2, E58, 29 mg, y=57%) as yellow solid.NMR: ¹H NMR (DMSO-d₆) δ:10.15 (br. s., 1H), 8.57 (s, 1H), 7.66 (d, 1H),7.51 (br. s., 1H), 7.38-7.46 (m, 1H), 3.69 (s, 4H), 3.47-3.63 (m, 2H),3.35-3.46 (m, 1H), 3.11-3.27 (m, 4H), 2.94-3.08 (m, 1H), 2.41-2.47 (m,1H), 2.38 (s, 3H), 2.02-2.15 (m, 2H), 1.52-1.68 (m, 2H), 1.40-1.50 (m,1H), 1.28-1.38 (m, 1H), MS (m/z): 496.4 [MH]⁺.

Example 59:(1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E59)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (TRANS, p36,55 mg, 0.227 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 68 mg, 0.25 mmol), Na₂CO₃ (29 mg, 0.27 mmol) and NaI (40 mg, 0.27mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E59, 23 mg, y=21%). NMR: ¹H NMR (Acetone-d6) δ: 8.30 (s, 1H),7.32 (s, 3H), 3.82 (s, 3H), 3.37-3.53 (m, 3H), 2.79-2.84 (m, 2H), 2.44(s, 3H), 2.33-2.41 (m, 1H), 2.13-2.22 (m, 2H), 1.79-1.90 (m, 2H),1.51-1.72 (m, 3H), 1.28-1.44 (m, 3H). MS (m/z): 478.3 [M]⁺.

Example 60:(1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E60)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (CIS, p37,55 mg, 0.227 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 68 mg, 0.249 mmol), Na₂CO₃ (29 mg, 0.272 mmol) and NaI (40 mg,0.272 mmol) in DMF (0.13 mL) affording(1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E60, 37 mg, y=34%). NMR: ¹H NMR (Acetone-d₆) δ: 8.28 (s, 1H),7.27-7.31 (m, 1H), 7.22 (s, 2H), 3.78 (s, 3H), 3.25-3.36 (m, 2H),2.78-2.85 (m, 3H), 2.43 (s, 3H), 2.24-2.39 (m, 2H), 2.08 (br. s., 2H),1.97 (d, 4H), 1.22-1.52 (m, 3H). MS (m/z): 477.9 [M]⁺.

Example 61:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, E61)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, p52, 40 mg, 0.165 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 50 mg, 0.18 mmol), Na₂CO₃ (21 mg, 0.2 mmol) and NaI (30 mg, 0.2mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, E61, 34 mg, y=43%). NMR: ¹H NMR (Acetone-d₆) δ: 8.62 (s, 1H), 8.28(s, 1H), 7.69-7.85 (m, 2H), 3.77 (s, 3H), 3.16-3.37 (m, 2H), 2.73 (br.s., 1H), 2.47-2.71 (m, 4H), 2.44 (s, 3H), 2.26-2.34 (m, 1H), 2.09-2.15(m, 2H), 1.94-2.04 (m, 2H), 1.80-1.93 (m, 2H), 1.35-1.43 (m, 1H),1.27-1.34 (m, 1H). MS (m/z): 479.4 [MH]⁺.

Example 62:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E62)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 63 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.25 mmol) and NaI (38 mg,0.25 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E62, 49 mg, y=49%). NMR: ¹H NMR (CDCl₃) δ: 7.56 (d, 2H),7.09-7.26 (d, 2H), 4.06-4.18 (m, 2H), 3.46-3.63 (m, 6H), 3.27 (s, 2H),2.66-3.05 (m, 6H), 2.00-2.34 (m, 6H), 1.81-1.97 (m, 3H), 1.26-1.38 (m,1H), 1.12-1.23 (m, 1H). MS (m/z): 481.5 [MH]⁺.

Example 63 and Example 64: (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E63, Enantiomer 1) and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E64, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E62, 49 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 80/20 v/v Flowrate (ml/min) 16 ml/min DAD detection 220 nm Loop 500 μL Injection 11.5mg/injection

affording (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E63, 18 mg) Enantiomer 1: ret. time 7.6 min, 100% ee, MS (m/z): 481.5[MH]⁺ and (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E64, 19 mg), Enantiomer 2: ret. time 9.1 min, 100% ee, MS (m/z): 481.5[MH]⁺.

Example 65: (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E65, Enantiomer 1)

(1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E63, 18 mg) was treated with 1.2 eq of HCl in Et₂O affording (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, E65, 19 mg). MS (m/z): 481.5 [MH]⁺.

Example 66: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E66, Enantiomer 2)

(1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E64, 19 mg) was treated with 1.2 eq of HCl in Et₂O affording (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, E66, 20 mg). MS (m/z): 481.5 [MH]⁺.

Example 67:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E67)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 35 mg, 0.145 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 44 mg, 0.16 mmol), Na₂CO₃ (19 mg, 0.174 mmol) and NaI (26 mg,0.174 mmol) in DMF (0.14 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E67, 30 mg, y=43%). NMR: ¹H NMR (Acetone-d₆) δ: 7.63 (d, 2H), 7.41(s, 2H), 3.93-4.07 (m, 2H), 3.58 (s, 3H), 3.47-3.56 (m, 2H), 3.31-3.35(m, 1H), 3.05-3.23 (m, 3H), 2.42-2.71 (m, 5H), 2.20-2.30 (m, 1H),1.76-2.02 (m, 8H), 1.28-1.35 (m, 1H), 1.19-1.26 (m, 1H). MS (m/z): 481.4[MH]⁺.

Example 68 and Example 69:(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E68, Enantiomer 1) and(1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E69, Enantiomer 2)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E67, 28 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phase n-Hexane/Ethanol65/35% v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 1000μL Injection 14 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E68, 10.8 mg). Enantiomer 1: ret. time 8.4 min, 100% ee, MS (m/z):481.3 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E69, 10.7 mg). Enantiomer 2: ret. time 11.9 min, 100% ee. MS(m/z): 481.3 [MH]⁺.

Example 70:(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E70, CIS, Enantiomer 1)

(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E68, 10.8 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, CIS, E70, 11 mg). MS (m/z): 481.3[MH]⁺.

Example 71:(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E71)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p22, 50 mg, 0.193 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 58 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E71, 40 mg, y=41%). NMR: ¹H NMR (Acetone-d₆) δ: 7.50 (m, 2H),7.32 (br. s., 1H), 3.99 (d, 2H), 3.62 (s, 3H), 3.48-3.57 (m, 2H),3.19-3.28 (m, 2H), 3.07-3.17 (m, 1H), 2.53-2.74 (m, 6H), 2.29-2.36 (m,1H), 1.89 (br. s., 6H), 1.57-1.71 (m, 2H), 1.26-1.43 (m, 4H). MS (m/z):499.4 [MH]⁺.

Example 72 and Example 73: (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E72, TRANS, Enantiomer 1) and (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E73, TRANS, Enantiomer 2)

(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E71, 38 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 60/40% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 500 μL Injection 9.5 mg/injection

affording (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E72, 13 mg). Enantiomer 1: ret. time 8.1 min, 100% ee. MS (m/z):499.4 [MH]⁺ and (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E73, 13 mg). Enantiomer 2: ret. time 9.4 min, 98.8% ee. MS(m/z): 499.4 [MH]⁺.

Example 74: (1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E74, TRANS, Enantiomer 1)

(1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E72, 13 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3R or1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, TRANS, E74, 12 mg). MS (m/z): 499.4[MH]⁺.

Example 75: (1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E75, TRANS, Enantiomer 2)

(1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E73, 13.8 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S or1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, TRANS, E75, 12 mg). MS (m/z): 499.4[MH]⁺.

Example 76:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E76)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.193 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 58 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording the title compound(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E76, 45 mg, y=47%). NMR: ¹H NMR (Acetone-d₆) δ: 7.45-7.52 (m, 2H),7.35 (m, 1H), 3.98 (m, 2H), 3.46-3.59 (m, 5H), 3.03-3.21 (m, 4H),2.40-2.70 (m, 5H), 2.24-2.33 (m, 1H), 2.02 (d, 2H), 1.74-1.94 (m, 6H),1.39 (m, 1H), 1.25 (m, 1H). MS (m/z): 499.4 [MH]⁺.

Example 77 and Example 78:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E77, CIS, Enantiomer 1) and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(E78, CIS, Enantiomer 2)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E76, 42 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 70/30% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 1000 μL Injection 14 mg/injection

affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E77, 15 mg). Enantiomer 1: ret. time 8.2 min, 100% ee. MS (m/z):499.4 [MH]⁺ and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E78, 15 mg). Enantiomer 2: ret. time 9.5 min, 97% ee. MS (m/z):499.4 [MH]⁺.

Example 79:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloride (E79, CIS, Enantiomer 2)

(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E78, 15 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, CIS, E79, 16.6 mg). MS (m/z): 499.4[MH]⁺.

Example 80:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E80)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS, p19, 50 mg, 0.29mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 80 mg, 0.29 mmol), Na₂CO₃ (37 mg, 0.348 mmol) and NaI (52 mg,0.348 mmol) in DMF (0.2 mL) affording the title compound(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E80, 23 mg, y=19%). NMR: ¹H NMR (Acetone-d₆) δ: 7.24-7.35 (m, 2H),7.11-7.19 (m, 3H), 3.99 (m, 2H), 3.59 (s, 3H), 3.48-3.57 (m, 2H),3.06-3.22 (m, 3H), 2.34-2.71 (m, 5H), 2.14 (br. s., 1H), 2.11 (d, 1H),1.76-2.01 (m, 8H), 1.08-1.23 (m, 2H). MS (m/z): 413.4 [MH]⁺.

Example 81 and Example 82:(1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E81, CIS, Enantiomer 1) and(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(E82, CIS, Enantiomer 2)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E80, 22 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 62/38% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 700 μL Injection 7.4 mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E81, 8 mg). Enantiomer 1: ret. time 8.4 min, 100% ee. MS (m/z):413.4 [MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E82, 9 mg). Enantiomer 2: ret. time 10.3 min, 100% ee. MS (m/z):413.4 [MH]⁺.

Example 83:(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptanehydrochloride (E83, CIS, Enantiomer 2)

(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E82, 9 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, CIS, E83, 7.8 mg). MS (m/z): 413.4[MH]⁺.

Example 84:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, E84)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, p52, 60 mg, 0.247 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole(p149, 75 mg, 0.272 mmol), Na₂CO₃ (31 mg, 0.3 mmol) and NaI (44 mg, 0.3mmol) in DMF (0.2 mL) affording the title compound(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane(CIS, E84, 25 mg, y=21%). NMR: ¹H NMR (Acetone-d₆) δ: 8.62 (s, 1H),7.73-7.84 (m, 2H), 3.95-4.04 (m, 2H), 3.58 (s, 3H), 3.49-3.56 (m, 2H),3.05-3.25 (m, 4H), 2.46-2.74 (m, 5H), 2.28-2.37 (m, 1H), 2.10-2.19 (m,2H), 1.79-1.97 (m, 7H), 1.37-1.48 (m, 1H), 1.28-1.36 (m, 1H). MS (m/z):482.5 [MH]⁺.

Example 85:(1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E85)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazole(p150, 69 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording the title compound(1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E85, 54 mg, y=52%). NMR: ¹H NMR (Acetone-d₆) δ: 7.62 (d, 2H), 7.40(s, 2H), 4.33-4.48 (m, 2H), 3.57 (s, 3H), 3.28-3.46 (m, 2H), 3.03-3.22(m, 2H), 2.38-2.72 (m, 5H), 2.20-2.29 (m, 1H), 1.96 (d, 7H), 1.69-1.86(m, 5H), 1.27-1.35 (m, 1H), 1.17-1.25 (m, 1H). MS (m/z): 507.1 [MH]⁺.

Example 86 and Example 87:(1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E86, CIS, Enantiomer 1) and(1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E87, CIS, Enantiomer 2)

(1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E85, 54 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 60/40% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 2000 μL Injection 27 mg/injection

affording(1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E86, 24 mg). Enantiomer 1: ret. time 6.5 min, 100% ee. MS (m/z):507.4 [MH]⁺ and(1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E87, 23 mg). Enantiomer 2: ret. time 9.6 min, 100% ee. MS (m/z):507.4 [MH]⁺.

Example 88:(1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E88, CIS, Enantiomer 1)

(1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E86, 24 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, CIS, E88, 24.3 mg). MS (m/z): 507.4[MH]⁺.

Example 89:(1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E89)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-5-cyclohexyl-4-methyl-4H-1,2,4-triazole(p151, 63 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.25 mmol) and NaI (38 mg,0.25 mmol) in DMF (0.2 mL) affording the title compound(1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E89, 37 mg, y=37%). NMR: ¹H NMR (CDCl₃) δ: 7.51-7.66 (m, 2H),7.31-7.42 (m, 2H), 3.53 (s, 3H), 3.24 (m, 2H), 2.74-3.15 (m, 5H),2.58-2.71 (m, 1H), 2.09-2.41 (m, 3H), 1.95 (m, 4H), 1.68-1.84 (m, 5H),1.16-1.48 (m, 6H). MS (m/z): 479.5 [MH]⁺.

Example 90 and Example 91: (1R,3R or1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E90, TRANS, Enantiomer 1) and (1S,3S or1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E91, TRANS, Enantiomer 2)

(1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E89, 34 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 92/8 v/v Flow rate(ml/min) 16 ml/min DAD detection 220 nm Loop 750 μL Injection 8.5mg/injection

affording (1R,3R or1S,3S)-5-{(3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E90, 14 mg). Enantiomer 1: ret. time 8.8 min, 100% ee. MS (m/z):479.5 [MH]⁺ and (1S,3S or1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E91, 10.5 mg). Enantiomer 2: ret. time 10.5 min, 100% ee. MS(m/z): 479.5 [MH]⁺.

Example 92: (1R,3R or1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E92, TRANS, Enantiomer 1)

(1R,3R or1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E90, 14 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3R or1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, TRANS, E92, 15 mg). MS (m/z): 479.5[MH]⁺.

Example 93: (1S,3S or1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E93, TRANS, Enantiomer 2)

(1S,3S or1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E91, 10.5 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S or1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, TRANS, E93, 11 mg). MS (m/z): 479.5[MH]⁺.

Example 94:(1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E94)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-5-cyclohexyl-4-methyl-4H-1,2,4-triazole(p151, 63 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording the title compound(1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E94, 32 mg, y=32%). NMR: ¹H NMR (Acetone-d₆) δ: 7.63 (d, 2H), 7.39(d, 2H), 3.54 (s, 3H), 3.42 (m, 1H), 3.02-3.23 (m, 2H), 2.37-2.66 (m,4H), 2.35-2.67 (m, 1H), 2.18-2.31 (m, 2H), 1.96 (br. s., 4H), 1.83 (br.s., 5H), 1.54-1.67 (m, 2H), 1.27-1.51 (m, 4H), 1.17-1.25 (m, 1H). MS(m/z): 479.5 [MH]⁺.

Example 95 and Example 96:(1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E95, CIS, Enantiomer 1) and(1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E96, CIS, Enantiomer 2)

(1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E94, 30 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 85/15% v/v Flowrate (ml/min) 18 ml/min DAD detection 220 nm Loop 1000 μL Injection 15mg/injection

affording(1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E95, 12 mg). Enantiomer 1: ret. time 6.6 min, 100% ee. MS (m/z):479.5 [MH]⁺ and(1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E96, 11.5 mg). Enantiomer 2: ret. time 8.4 min, 100% ee. MS (m/z):479.5 [MH]⁺.

Example 97:(1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E97, CIS, Enantiomer 1)

(1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E95, 12 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 1, CIS, E97, 12.5 mg). MS (m/z): 479.5[MH]⁺.

Example 98:(1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E98, CIS, Enantiomer 2)

(1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E96, 11.5 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (Enantiomer 2, CIS, E98, 12.1 mg). MS (m/z): 479.1[MH]⁺.

Preparation 249: tert-butyl4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, p249)

(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.21 mmol), tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate(p224, 78 mg, 0.21 mmol), Na₂CO₃ (27 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) were dissolved in DMF (0.2 mL) and heated at 60° C. andshaken in a PLS apparatus at that temperature O/N. The mixture wasdiluted with water and extracted twice with DCM. The organic phase wasdried and evaporated. Crude material was purified by FC on silicacartridge (eluent from DCM to 100% MeOH) affording tert-butyl4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, p249, 63 mg, y=35%) that was used as such in the next step. MS(m/z): 580.4 [MH]⁺.

Preparation 250:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p250)

To a solution of tert-butyl4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(p249, CIS, 63 mg, 0.11 mmol) in DCM (2.5 mL), TFA (0.5 mL) was addedand the reaction was stirred at RT for 1.5 h. The reaction mixture wasconcentrated under vacuum. The residue was loaded on a SCX cartridge andeluted with MeOH/NH₃ 1M in MeOH to obtain(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p250, CIS, 42 mg, y=80%) as pale yellow gum. MS (m/z): 480.4 [MH]⁺.

Example 99:1-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(CIS, E99)

To a solution of(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p250, CIS, 42 mg, 0.088 mmol) in DCM (2 mL), Ac₂O (11 uL, 0.11 mmol)and Py (16 uL, 0.2 mmol) were added and the mixture was stirred at RTfor 1 h. The reaction mixture was diluted with water and extracted withDCM. Organic phase was dried and concentrated under reduced pressure toobtain1-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(E99, CIS, 38 mg, y=77%) as colourless oil. NMR: ¹H NMR (Acetone-d₆) δ:7.62 (d, 2H), 7.32-7.47 (m, 2H), 4.74-4.74 (m, 1H), 4.43-4.58 (m, 1H),3.93-4.08 (m, 1H), 3.59 (s, 3H), 3.28 (br. s., 5H), 2.82-2.95 (m, 2H),2.52 (br. s., 4H), 2.27 (br. s., 1H), 2.08-2.18 (m, 2H), 1.92-2.03 (m,4H), 1.85 (d, 2H), 1.60-1.73 (m, 1H), 1.17-1.39 (m, 3H). MS (m/z): 522.5[MH]⁺.

Preparation 251: tert-butyl4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, Enantiomer 1, p251)

(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 300 mg, 1.24 mmol), tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate(p224, 510 mg, 1.36 mmol), Na₂CO₃ (159 mg, 1.5 mmol) and NaI (225 mg,1.5 mmol) were dissolved in DMF (1.4 mL) and heated at 60° C. O/N.Further tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate(100 mg, 0.27 mmol) was added and the reaction was stirred at 60° C. for4 hrs. The mixture was diluted with water and extracted three times withDCM. The organic phase was dried and evaporated to obtain an oil thatwas purified by FC on Silica gel (eluting from DCM to MeOH 10%) toobtain a yellow foam that was dissolved in DCM (3 mL) and treated withMP-isocyanate resin, shaking for 1 h. The resin was filtered and washedwith DCM and MeOH. Solvent was evaporated affording tert-butyl4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, Enantiomer 1, p251, 550 mg) that was used as crude in the nextstep. MS (m/z): 580.5 [MH]⁺.

Preparation 252:(1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p252)

tert-butyl4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(p251, CIS, Enantiomer 1, 550 mg, 0.95 mmol), was dissolved in DCM (5mL) and TFA (1 mL) was added. The resulting solution was stirred at RTfor 1 h, then the solvent was evaporated and the residue material waspurified by SCX cartridge (eluent MeOH/NH₃ 1M in MeOH) to obtain(1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p252, CIS, Enantiomer 1, 232 mg, y=48%) as yellow sticky oil. MS (m/z):480.4 [MH]⁺.

Example 100:1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(CIS, Enantiomer 1, E100)

To a solution of(1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p252, CIS, Enantiomer 1, 232 mg, 0.48 mmol) in DCM (5 mL), Ac₂O (55 uL,0.576 mmol) and Py (89 uL, 1.1 mmol) were added and the mixture wasstirred at RT for 1 h. The reaction mixture was diluted with water andextracted several time with DCM. Organic phase was dried andconcentrated under reduced pressure. The crude material was purified byFC on NH cartridge (eluting from cHex to EtOAc 100%, then to MeOH 100%)to obtain1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(E100, CIS, Enantiomer 1, 198 mg, y=79%) as colourless sticky oil. NMR:¹H NMR (DMSO-d₆) δ: 7.60 (d, 2H), 7.31 (d, 2H), 4.36 (d, 1H), 3.87 (d,1H), 3.47 (s, 3H), 3.13-3.22 (m, 1H), 2.95-3.11 (m, 3H), 2.74 (td, 1H),2.62-2.69 (m, 1H), 2.30-2.48 (m, 4H), 2.19 (dd, 1H), 2.02 (s, 3H),1.80-1.97 (m, 5H), 1.61-1.73 (m, 3H), 1.42-1.53 (m, 1H), 1.22-1.28 (m,1H), 1.16 (dd, 1H). MS (m/z): 522.4 [MH]⁺.

Preparation 253: tert-butyl4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, p253)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.193 mmol), tert-butyl4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate(p224, 76 mg, 0.2 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg, 0.23mmol) in DMF (0.2 mL) affording the title compound tert-butyl4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, p253, 38 mg, y=33%) that was used as such in the next step. MS(m/z): 598.6 [MH]⁺.

Preparation 254:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, p254)

To a stirred solution of tert-butyl4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate(CIS, p253, 37 mg, 0.062 mmol) in DCM (3 mL) TFA (0.3 mL) was added andthe resulting reaction solution was left stirring at RT for 1 h. Solventwas removed in vacuo and the residue was charged on SCX eluting with 1MNH₃ in MeOH to afford after evaporation(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(p254, 28 mg, y=91%). That was used as such in the next step. MS (m/z):498.5 [MH]⁺.

Example 101:1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(CIS, E101)

To a solution of(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(p254, CIS, 28 mg, 0.056 mmol) in DCM (1.25 mL), Ac₂O (6 uL, 0.067 mmol)and Py (10 uL, 0.129 mmol) were added and the mixture was stirred at RTO/N. The reaction mixture was diluted with water and extracted with DCM.Organic phase was dried and concentrated under reduced pressure. Crudematerial was purified by FC on silica gel (eluent: DCM to 100% MeOH)affording1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(E101, CIS, 17 mg, y=56%). NMR: ¹H NMR (Acetone-d₆) δ: 7.43-7.54 (m,2H), 7.35 (s, 1H), 4.44-4.56 (m, 1H), 3.98-4.05 (m, 1H), 3.57-3.65 (m,3H), 3.05-3.35 (m, 4H), 2.72-2.87 (m, 4H), 2.40-2.68 (m, 4H), 2.24-2.33(m, 1H), 1.57-2.06 (m, 10H), 1.21-1.40 (m, 2H). MS (m/z): 540.4 [MH]⁺.

Example 102:1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl})sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-onehydrochloride (CIS, E102)

The compound was prepared as in Example 1, reacting(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p24, 25 mg, 0.096 mmol),1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-1-yl)ethan-1-one(p222, 32 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording the title compound 1-{4-[5-({3-[(1S,3Sor1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one(CIS, Enantiomer 1, 24 mg) that was dissolved in DCM and Et₂O andsalified by 1.2 eq of HCl 2M in Et₂O to obtain1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-onehydrochloric salt (E102, Enantiomer 1, 22.7 mg, y=42%) as yellow solid.NMR: ¹H NMR (DMSO-d₆) δ: 10.16-10.73 (m, 1H), 7.67 (d, 1H), 7.52 (s,1H), 7.33-7.42 (m, 1H), 4.33-4.44 (m, 1H), 3.82-3.96 (m, 1H), 3.69-3.76(m, 1H), 3.45-3.51 (m, 3H), 3.03-3.37 (m, 9H), 2.58-2.83 (m, 2H),2.20-2.31 (m, 1H), 2.05-2.16 (m, 1H), 2.02 (s, 3H), 1.94-2.01 (m, 2H),1.88 (br. s., 2H), 1.58-1.74 (m, 1H), 1.41-1.57 (m, 2H), 1.20-1.38 (m,2H). MS (m/z): 540.4 [MH]⁺.

Example 103:3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one(CIS, Enantiomer 1, E103)

To a solution of(1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p252, CIS, Enantiomer 1, 37 mg, 0.077 mmol) 1-Hydroxybenzotriazolehydrate (11 mg, 0.081 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 mg, 0.078 mmol), 3-Methoxypropionic acid(8 uL, 0.077 mmol) and TEA (32 uL, 0.23 mmol) in DCM (2 mL) was addedand the mixture was stirred at RT O/N. Then it was washed with NaHCO₃(×1), NH₄Cl (×3) and Brine, dried and concentrated under reducedpressure. Crude was purified by FC on NH column (eluent: Cy to 100%AcOEt) affording3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one(E103, CIS, Enantiomer 1, 24 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ:7.58-7.68 (m, 2H), 7.33-7.43 (m, 2H), 4.49-4.57 (m, 1H), 4.03-4.14 (m,1H), 3.65 (s, 2H), 3.60 (s, 3H), 3.23-3.34 (m, 4H), 3.05-3.23 (m, 3H),2.84-2.90 (m, 1H), 2.69-2.76 (m, 1H), 2.57-2.68 (m, 3H), 2.51 (s, 3H),2.20-2.26 (m, 1H), 1.98 (s, 5H), 1.63-1.90 (m, 4H), 1.26-1.32 (m, 1H),1.18-1.24 (m, 1H). MS (m/z): 566.5 [MH]⁺.

Example 104:3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-onehydrochloride (CIS, Enantiomer 1, E104)

3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one(E103, CIS, Enantiomer 1, 24 mg) was dissolved in MeOH/Et₂O and treatedwith HCl 2M in Et₂O (1.1 eq) to form the corresponding hydrochloridesalt. Solvent was eliminated under reduced pressure; the solid wastriturated with Et₂O and dried under high vacuum affording3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-onehydrochloride (E104, CIS, Enantiomer 1, 23.4 mg). MS (m/z): 566.5 [MH]⁺.

Example 105:(1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E105)

To a solution of(1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p252, CIS, Enantiomer 1, 37 mg, 0.077 mmol) 1-Hydroxybenzotriazolehydrate (11 mg, 0.081 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 mg, 0.078 mmol), cyclopropanecarboxylicacid (7 uL, 0.077 mmol) and TEA (32 uL, 0.23 mmol) in DCM (2 mL) wereadded and the mixture was stirred at RT O/N. Then it was washed withNaHCO₃ (×1), NH₄Cl (×3) and Brine, dried and concentrated under reducedpressure. Crude was purified by FC on NH column (eluent: Cy to 100%AcOEt) affording(1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E105, CIS, Enantiomer 1, 35 mg, y=83%). NMR: ¹H NMR (Acetone-d₆) δ:7.58-7.68 (m, 2H), 7.36-7.44 (m, 2H), 4.37-4.57 (m, 2H), 3.60 (s, 3H),3.32-3.45 (m, 1H), 3.05-3.24 (m, 3H), 2.85-2.97 (m, 1H), 2.69-2.76 (m,1H), 2.57-2.65 (m, 1H), 2.40-2.53 (m, 3H), 2.19-2.27 (m, 1H), 1.89-2.05(m, 6H), 1.64-1.84 (m, 4H), 1.26-1.31 (m, 1H), 1.18-1.24 (m, 1H), 0.83(d, 2H), 0.73 (d, 2H). MS (m/z): 548.5 [MH]⁺.

Example 106:(1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E106)

(1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(E105, CIS, Enantiomer 1, 35 mg) was dissolved in MeOH/Et₂O and treatedwith HCl 2M in Et₂O (1.1 eq) to form the corresponding hydrochloridesalt. Solvent was eliminated under reduced pressure; the solid wastriturated with Et₂O and dried under high vacuum affording(1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (E106, CIS, Enantiomer 1, 30.8 mg). MS (m/z): 548.4 [MH]⁺.

Preparation 255: tert-butyl3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidine-1-carboxylate(CIS, p255)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol), tert-butyl3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}azetidine-1-carboxylate(p226, 46 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording the title compound tert-butyl3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidine-1-carboxylate(CIS, p255, 37 mg, y=37%) that was used as such in the next step. MS(m/z): 552.5 [MH]⁺.

Preparation 256:(1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p256)

To a solution of tert-butyl3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidine-1-carboxylate(p255, 37 mg, 0.11 mmol) in DCM (2 mL), TFA (0.5 mL) was added and thereaction was stirred at RT for 1.5h. The reaction mixture wasconcentrated under vacuum. The residue was loaded on a SCX cartridge andeluted with MeOH/NH₃ 1M in MeOH to obtain(1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p256, CIS, 25 mg, y=82%) as pale yellow gum. MS (m/z): 452.4 [MH]⁺.

Example 107:1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}ethan-1-one(CIS, E107)

To a solution of(1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p256, CIS, 25 mg, 0.055 mmol) in DCM (1.25 mL), Ac₂O (6 uL, 0.066 mmol)and Py (10 uL, 0.127 mmol) were added and the mixture was stirred at RTO/N. The reaction mixture was diluted with water and extracted with DCM.Organic phase was dried and concentrated under reduced pressure. Thecrude was purified by FC on silica cartridge (eluent from DCM to MeOH)to obtain1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}ethan-1-one(E107, CIS, 7.2 mg, y=27%) as colourless gum. NMR: ¹H NMR (Acetone-d₆)δ: 7.63 (d, 2H), 7.39 (d, 2H), 4.51-4.65 (m, 2H), 4.26-4.35 (m, 1H),4.15-4.23 (m, 1H), 4.00-4.12 (m, 1H), 3.51 (s, 3H), 3.06-3.26 (m, 3H),2.68-2.76 (m, 1H), 2.57-2.67 (m, 1H), 2.42-2.56 (m, 3H), 2.20-2.30 (m,2H), 1.89-2.04 (m, 2H), 1.82 (s, 4H), 1.27-1.37 (m, 2H), 1.17-1.25 (m,1H). MS (m/z): 494.4 [MH]⁺.

Preparation 257: tert-butylN-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate(CIS, p257)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 40 mg, 0.17 mmol), tert-butylN-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl})cyclohexyl)carbamate (p230, 66 mg, 0.17 mmol), Na₂CO₃ (22 mg, 0.2 mmol)and NaI (25 mg, 0.17 mmol) in DMF (0.3 mL) affording tert-butylN-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate(CIS, p257, 33 mg, y=33%) that was used as such in the next step. MS(m/z): 594.5 [MH]⁺.

Example 108:4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine(CIS, E108)

To a solution of tert-butylN-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate(CIS, p257, 33 mg, 0.056 mmol) in DCM (0.2 mL), at RT, TFA (0.085 mL)was added and the resulting mixture was left reacting at RT. After 1.5 hthe mixture was concentrated under vacuum and the residue was taken upwith DCM. The solution was washed with aqueous concentrated sodiumbicarbonate solution, water, dried over sodium sulphate and the solventremoved under reduced pressure to give4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine(E108, CIS, 24 mg, y=87%). NMR: ¹H NMR (CDCl₃) δ: 7.53 (d, 2H), 7.20 (d,2H), 3.44 (s, 3H), 3.19 (d, 2H), 2.99-3.07 (m, 1H), 2.73-2.84 (m, 2H),2.57-2.66 (m, 1H), 2.50 (s, 2H), 2.39 (s, 1H), 2.11 (d, 2H), 1.93-2.08(m, 4H), 1.88 (d, 2H), 1.71-1.82 (m, 7H), 1.15-1.23 (m, 2H). MS (m/z):494.4 [MH]⁺.

Example 109:N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamidehydrochloride (CIS, E109)

To a solution of4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine(E108, CIS, 24 mg, 0.049 mmol) and DIPEA (0.020 mL, 0.12 mmol) in DCM(0.2 mL), at RT, Ac₂O (0.005 mL, 0.053 mmol) was added and the resultingreaction mixture was left to react for 24 hrs. The mixture was dilutedwith DCM and washed twice with aqueous saturated sodium carbonate. Theorganic phase was washed with water, dried over sodium sulfate and thesolvent removed under reduced pressure to giveN-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(CIS, 20 mg). The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether(0.021 mL) was added and the reaction mixture was concentrated undervacuum. The solid so obtained was triturated with ether and dried undervacuum at 40° C. O/N, affordingN-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamidehydrochloride (E109, CIS, 21 mg, y=75%). NMR: ¹H NMR (DMSO-d₆) δ:10.79-11.23 (m, 1H), 7.83-7.91 (m, 1H), 7.67 (d, 2H), 7.45 (d, 2H),3.83-3.91 (m, 1H), 3.59-3.72 (m, 1H), 3.55 (s, 3H), 3.34-3.46 (m, 1H),3.00-3.33 (m, 7H), 2.56-2.66 (m, 1H), 2.35-2.44 (m, 1H), 2.17-2.32 (m,1H), 1.87-1.98 (m, 3H), 1.85 (s, 3H), 1.68-1.79 (m, 4H), 1.54-1.67 (m,2H), 1.35-1.53 (m, 2H), 1.22-1.33 (m, 2H). MS (m/z): 536.5 [MH]⁺.

Example 110 and 111:N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(CIS, Enantiomer 1, E110) andN-{4-[4-methyl-5-({3-[(1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(CIS, Enantiomer 2, E111)

To a solution of4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine(E108, 69 mg, 0.14 mmol) and DIPEA (0.061 mL, 0.35 mmol) in DCM (0.5mL), at RT, Ac₂O (0.016 mL, 0.16 mmol) was added and the resultingreaction mixture was left to react for 24 hrs. The mixture was dilutedwith DCM and washed with aqueous saturated ammonium chloride; thesolvent was removed under reduced pressure. The crude material waspurified by FC on silica gel (DCM/MeOH from 100/0 to 55/45) to give 73mg of racemic product that was submitted to chiral prep HPLC

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol + 0.1% isopropylamine) 85/15% v/v Flow rate(ml/min) 16 ml/min DAD detection 220 nm Loop 350 μL Injection 10mg/injection

affordingN-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(E110, CIS, 24 mg). Enantiomer 1: ret. time 8.7 min, 100% ee. MS (m/z):536.6 [MH]⁺ andN-{4-[4-methyl-5-({3-[(1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(E111, CIS, 24 mg). Enantiomer 2: ret. time 10.7 min, 98.2% ee. MS(m/z): 536.6 [MH]⁺.

Example 112:N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamidehydrochloride (E112, CIS, Enantiomer 1)

N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide(E10, CIS, 24 mg) was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.025mL) was added and the mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 40° C.overnight, affordingN-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamidehydrochloride (E112, Enantiomer 1, 23 mg). MS (m/z): 536.4 [MH]⁺.

Example 113:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E113)

The compound was prepared as in Example 1, reacting (1S,3S or1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13,50 mg, 0.207 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}morpholine(p152, 63 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.25 mmol) and NaI (37 mg,0.25 mmol) in DMF (0.2 mL) affording the title compound(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E113, 7.7 mg, y=8%). NMR: ¹H NMR (Acetone-d₆) δ: 7.64 (d, 2H),7.36 (d, 2H), 3.74-3.84 (m, 4H), 3.49 (s, 3H), 3.09-3.23 (m, 6H), 2.72(d, 1H), 2.49-2.63 (m, 5H), 2.21-2.31 (m, 1H), 2.09 (br. s., 1H), 1.89(s, 2H), 1.59-1.70 (m, 1H), 1.37-1.49 (m, 1H), 1.24-1.29 (m, 1H),1.19-1.24 (m, 1H). MS (m/z): 482.5 [MH]⁺.

Example 114:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E114)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E113, 7.7 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, E114, 8 mg). MS (m/z): 482.5 [MH]⁺.

Example 115:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E115)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.2 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}morpholine(p152, 59 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.231 mmol) and NaI (35 mg,0.231 mmol) in DMF (0.2 mL) affording the title compound(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E115, 45 mg, y=47%). NMR: ¹H NMR (CDCl₃) δ: 7.55 (d, 2H), 7.23 (d,2H), 3.82-3.91 (m, 4H), 3.39 (s, 3H), 3.09-3.25 (m, 6H), 2.39-2.96br.s., 5H), 2.12-2.22 (m, 2H), 1.87-2.08 (m, 4H), 1.18-1.28 (m, 2H). MS(m/z): 482.5 [MH]⁺.

Example 116 and 117:(1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E116) and(1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E117)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E115, 40 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 60/40% v/v Flow rate (ml/min) 17 ml/min DADdetection 220 nm Loop 1000 μL Injection 20 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E116, 10.8 mg). Enantiomer 1: ret. time 6.2 min, 100% ee. MS(m/z): 482.5 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E117, 9.8 mg). Enantiomer 2: ret. time 10.0 min, 100% ee. MS(m/z): 482.5 [MH]⁺.

Example 118:(1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E118)

(1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E116, 10.8 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, E118, 11 mg). MS (m/z): 482.5 [MH]⁺.

Example 119:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-onehydrochloride (CIS, Enantiomer 1, diastereomeric mixture, E119)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one(p153, 32 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording the title compound4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one(CIS, Enantiomer 1, 23.7 mg).

The latter was dissolved with DCM/Et₂O and treated with 1.2 eq of HCl inEt₂O affordingN4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-onehydrochloride (E119, CIS, Enantiomer 1, 19 mg, y=36%) as diastereomericmixture. NMR: ¹H NMR (DMSO-d₆) δ: 9.96-10.25 (m, 1H), 7.68 (d, 2H), 7.60(br. s., 1H), 7.44 (br. s., 2H), 3.59-3.76 (m, 2H), 3.50 (s, 3H), 3.40(br. s., 2H), 3.11 (br. s., 5H), 2.40-2.48 (m, 3H), 2.19-2.31 (m, 2H),1.87-2.16 (m, 4H), 1.71-1.85 (m, 2H), 1.26-1.55 (m, 3H). MS (m/z): 494.5[MH]⁺.

Example 120:1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one(CIS, Enantiomer 1, diastereomeric mixture, E120)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methylpiperidin-2-one(p154, 35 mg, 0.113 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg,0.12 mmol) in DMF (0.1 mL) affording the title compound1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one(CIS, Enantiomer 1, E120, 28.8 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ:7.63 (s, 2H), 7.33-7.46 (m, 2H), 3.62 (s, 3H), 3.35-3.52 (m, 3H),3.04-3.25 (m, 2H), 2.91 (s, 3H), 2.33-2.74 (m, 7H), 2.19-2.31 (m, 2H),1.69-2.06 (m, 6H), 1.20-1.36 (m, 2H). MS (m/z): 508.4 [MH]⁺.

Example 121:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-onehydrochloride (CIS, Enantiomer 1, diastereomeric mixture, E121)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.103 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one(p155, 33 mg, 0.113 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg,0.12 mmol) in DMF (0.1 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one(CIS, Enantiomer 1, 12 mg).

The latter was dissolved with DCM/Et₂O and treated with 1.2 eq of HCl inEt₂O affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-onehydrochloride (E121, CIS, Enantiomer 1, 10 mg, y=18%) as diastereomericmixture. NMR: ¹H NMR (DMSO-d₆) δ: 10.40-10.71 (m, 1H), 7.57-7.74 (m,3H), 7.44 (d, 2H), 3.61-3.74 (m, 1H), 3.54 (s, 3H), 2.88-3.45 (m, 10H),2.18-2.67 (m, 4H), 1.84-2.16 (m, 5H), 1.25-1.55 (m, 2H). MS (m/z): 494.3[MH]⁺.

Preparation 258:(1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p258)

To a solution of(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p14,56 mg, 0.23 mmol) in THF (0.4 mL), in a vial, DIPEA (0.12 mL, 0.69 mmol)and 1-bromo-3-chloropropane (0.21 mL, 2.07 mmol) were added, the vialwas sealed and the resulting mixture was shaken at 65° C. for 3 hrs.After cooling at RT the reaction mixture was diluted with EA andfiltered. The filtrate was concentrated under reduced pressure and thecrude material was purified by FC on silica gel (eluting with DCM/MeOHfrom 100/0 to 96/4) affording(1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p258, 51 mg, y=68%) as pale yellow oil. MS (m/z): 318.3 [MH]⁺.

Example 122:6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E122)

A sealed vial containing a mixture of(1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p258, CIS, 25 mg, 0.079 mmol),6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydropyridin-2-one(p72, 18 mg, 0.087 mmol), Na₂CO₃ (10 mg, 0.095 mmol) and NaI (12 mg,0.079 mmol) and DMF (0.2 mL) was shaken O/N at 60° C. in a PLSapparatus. The mixture was diluted with DCM, the organic phase waswashed twice with water, dried over sodium sulfate and the solventremoved under reduced pressure. The crude material was purified by FC onsilica gel (eluting with DCM/MeOH from 100/0 to 50/50) to give6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E122, 26 mg, y=66%). NMR: ¹H NMR (DMSO-d₆) δ: 11.06-11.17 (m, 1H),7.73-7.81 (m, 1H), 7.56-7.67 (m, 2H), 7.29-7.46 (m, 3H), 6.68-6.76 (m,1H), 3.86 (s, 3H), 3.14 (d, 2H), 2.64-2.78 (m, 1H), 2.36-2.50 (m, 4H),2.18-2.26 (m, 1H), 1.83-2.01 (m, 3H), 1.75 (m, 2H), 1.23-1.31 (m, 1H),1.14-1.23 (m, 1H). MS (m/z): 490.4 [MH]⁺.

Example 123:6-[5-({3-[(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E123)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p13, TRANS, 30 mg, 0.12 mmol),6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p156, 38 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.13 mL) affording6-[5-({3-[(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E123, 30 mg, y=44%). NMR: ¹H NMR (Acetone-d₆) δ: 7.75-7.82 (m,1H), 7.51-7.57 (m, 1H), 7.45-7.51 (m, 2H), 7.26-7.32 (m, 1H), 6.72-6.77(m, 1H), 3.97 (s, 3H), 3.33 (m, 2H), 2.75 (d, 1H), 2.63-2.70 (m, 2H),2.53-2.63 (m, 3H), 2.26-2.33 (m, 1H), 1.93-2.00 (m, 2H), 1.57-1.67 (m,1H), 1.23-1.39 (m, 3H). MS (m/z): 508.0 [MH]⁺.

Example 124:3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E124)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p14,CIS, 30 mg, 0.116 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p157, 36 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (21 mg,0.144 mmol) in DMF (0.2 mL) affording3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E124, 23 mg, y=40%). NMR: ¹H NMR (CDCl3) δ: 7.64-7.72 (m, 1H),7.50-7.59 (m, 3H), 7.17-7.25 (m, 2H), 6.32-6.39 (m, 1H), 3.46 (s, 3H),3.17-3.25 (m, 2H), 2.76-2.85 (m, 1H), 2.57-2.65 (m, 1H), 2.46-2.54 (m,2H), 2.42 (d, 1H), 2.10-2.16 (m, 2H), 1.81-2.02 (m, 4H), 1.16-1.23 (m,2H). MS (m/z): 490.4 [MH]⁺.

Example 125:3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E125)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p15, CIS,Enantiomer 1, 25 mg, 0.1 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p157, 32 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (15 mg, 0.1mmol) in DMF (0.2 mL) affording3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(25 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (1.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.overnight affording3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E125, 26 mg, y=49%) as white solid.NMR: ¹H NMR (DMSO-d₆) δ: 12.22 (br. s., 1H), 10.23-10.66 (m, 1H), 7.74(m, 1H), 7.61-7.69 (m, 3H), 7.36-7.49 (m, 2H), 6.38 (m, 1H), 2.59-3.79(m, 11H), 2.25 (m, 5H), 1.23-1.56 (m, 2H). MS (m/z): 490.4 [MH]⁺.

Example 126:5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E126)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p13,TRANS, 50 mg, 0.207 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 65 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E126, 48 mg, y=47%). NMR: ¹H NMR (Acetone-d₆) δ: 7.87 (d, 1H),7.75-7.83 (m, 1H), 7.64 (d, 2H), 7.35 (d, 2H), 6.52 (d, 1H), 3.71 (s,3H), 3.29 (m, 2H), 2.75 (d, 2H), 2.53-2.67 (m, 5H), 2.23-2.32 (m, 1H),1.90-2.00 (m, 2H), 1.61-1.73 (m, 1H), 1.37-1.49 (m, 1H), 1.27 (d, 1H),1.22 (d, 1H). MS (m/z): 490.4 [MH]⁺.

Example 127:5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E127)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p14,CIS, 35 mg, 0.15 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 43 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E127, 33 mg, y=45%). NMR: ¹H NMR (DMSO-d₆) δ:11.96-12.10 (m, 1H),7.68-7.80 (m, 2H), 7.55-7.64 (m, 2H), 7.27-7.36 (m, 2H), 6.44-6.53 (m,1H), 3.52 (s, 3H), 3.01-3.15 (m, 2H), 2.68 (br. s., 1H), 2.33-2.48 (m,4H), 2.16-2.26 (m, 1H), 1.81-2.02 (m, 3H), 1.73 (m, 2H), 1.27 (m, 1H),1.18 (m, 1H). MS (m/z): 490.5 [MH]⁺.

Example 128:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E128)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p15, CIS,Enantiomer 1, 35 mg, 0.15 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 43 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E128, 23 mg, y=31%). NMR: ¹H NMR (Acetone-d₆) δ:7.87-7.91 (m, 1H), 7.73-7.79 (m, 1H), 7.61 (d, 2H), 7.37 (d, 2H),6.46-6.52 (m, 1H), 3.66 (s, 3H), 3.10-3.27 (m, 3H), 2.68-2.78 (m, 2H),2.56-2.65 (m, 1H), 2.47 (s, 3H), 2.18-2.27 (m, 1H), 1.92-2.02 (m, 2H),1.75-1.87 (m, 2H), 1.25-1.30 (m, 1H), 1.17-1.22 (m, 1H). MS (m/z): 490.5[MH]⁺.

Example 129:5-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E129)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p23, CIS, 50 mg, 0.193 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 60 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording5-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E129, 17.8 mg, y=18%). NMR: ¹H NMR (Acetone-d₆) δ: 10.73-10.95 (m,1H), 7.84 (m, 1H), 7.77 (m, 1H), 7.43-7.52 (m, 2H), 7.27-7.39 (m, 1H),6.51 (m, 1H), 3.66 (s, 3H), 3.10-3.34 (m, 2H), 2.75 (br. s., 1H),2.38-2.67 (m, 4H), 2.19-2.33 (m, 1H), 1.92-2.03 (m, 3H), 1.73-1.87 (m,2H), 1.31-1.38 (m, 1H), 1.19-1.28 (m, 1H). MS (m/z): 508.4 [MH]⁺.

Example 130:5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E130)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (p29, CIS,50 mg, 0.24 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 74 mg, 0.26 mmol), Na₂CO₃ (31 mg, 0.28 mmol) and NaI (43 mg,0.288 mmol) in DMF (0.2 mL) affording5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E130, 38 mg, y=34%). NMR: ¹H NMR (Acetone-d₆) δ: 7.83-7.88 (m,1H), 7.74-7.79 (m, 1H), 7.08-7.18 (m, 1H), 6.88-7.03 (m, 2H), 6.47-6.54(m, 1H), 3.66 (s, 3H), 3.13-3.27 (m, 2H), 2.60 (d, 1H), 2.48 (m, 2H),2.35 (d, 1H), 2.08-2.13 (m, 2H), 1.92-2.00 (m, 3H), 1.77-1.86 (m, 2H),1.17-1.24 (m, 1H), 1.10-1.16 (m, 1H). MS (m/z): 458.3 [MH]⁺.

Example 131:5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E131)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (p33, CIS, 50mg, 0.26 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 83 mg, 0.29 mmol), Na₂CO₃ (33 mg, 0.31 mmol) and NaI (47 mg, 0.31mmol) in DMF (0.2 mL) affording5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E131, 30 mg, y=26%). NMR: ¹H NMR (Acetone-d₆) δ: 7.82-7.87 (m,1H), 7.75-7.81 (m, 1H), 7.16-7.21 (m, 2H), 7.03 (s, 2H), 6.47-6.54 (m,1H), 3.67 (s, 3H), 3.12-3.26 (m, 2H), 2.59-2.74 (m, 3H), 2.48 (s, 2H),2.35 (s, 1H), 1.91-2.01 (m, 2H), 1.76-1.87 (m, 2H), 1.11 (s, 2H). MS(m/z): 440.4 [MH]⁺.

Example 132:5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E132)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p40,TRANS, 30 mg, 0.124 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p158, 35 mg, 0.124 mmol), Na₂CO₃ (16 mg, 0.15 mmol) and NaI (19 mg,0.124 mmol) in DMF (0.2 mL) affording5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E132, 25 mg, y=41%). NMR: ¹H NMR (CDCl₃) δ: 7.71-7.80 (m, 2H),7.66 (d, 1H), 7.46 (m, 1H), 7.26-7.32 (m, 1H), 7.09 (d, 1H), 6.65-6.80(m, 1H), 3.59 (s, 3H), 3.35 (m, 2H), 2.48-2.95 (m, 5H), 2.27-2.44 (m,2H), 1.91-2.09 (m, 2H), 1.45-1.61 (m, 1H), 1.12-1.34 (m, 3H). MS (m/z):490.4 [MH]⁺.

Example 133:1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E133)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p15, CIS,Enantiomer 1, 35 mg, 0.15 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2-dihydropyridin-2-one(p159, 50 mg, 0.165 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg,0.18 mmol) in DMF (0.2 mL) affording1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(45 mg) that was dissolved in Et₂O (0.5 mL) and treated with 1.1 eq of2N HCl in ether. Solvent was eliminated under vacuum and the solid soobtained was triturated with ether and dried under vacuum affording1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E133, 46.8 mg, y=58%). NMR: ¹H NMR(DMSO-d₆) δ: 10.36 (s, 1H), 10.14-10.15 (m, 1H), 8.17 (br. s., 1H),7.61-7.79 (m, 3H), 7.45 (d, 2H), 6.55 (d, 1H), 3.71 (br. s., 2H),3.48-3.64 (m, 6H), 3.24-3.47 (m, 2H), 3.18 (d, 4H), 2.99 (br. s., 1H),2.26 (d, 1H), 1.88-2.18 (m, 3H), 1.25-1.54 (m, 2H). MS (m/z): 504.5[MH]⁺.

Example 134:4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E134)

The compound was prepared as in Example 1, reacting(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p14,CIS, 40 mg, 0.17 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p160, 48 mg, 0.17 mmol), Na₂CO₃ (22 mg, 0.2 mmol) and NaI (25 mg, 0.17mmol) in DMF (0.25 mL) affording4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, E134, 14 mg, y=17%). NMR: ¹H NMR (DMSO-d₆) δ: 7.61 (d, 2H), 7.54(d, 1H), 7.32 (d, 2H), 6.63 (d, 1H), 6.46-6.53 (m, 1H), 3.61 (s, 3H),3.07-3.19 (m, 2H), 2.65-2.74 (m, 1H), 2.35-2.49 (m, 5H), 2.17-2.24 (m,1H), 1.83-1.98 (m, 3H), 1.70-1.79 (m, 2H), 1.24-1.30 (m, 1H), 1.13-1.21(m, 1H). MS (m/z): 490.4 [MH]⁺.

Example 135:4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E135)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p40,TRANS, 30 mg, 0.124 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one(p160, 35 mg, 0.124 mmol), Na₂CO₃ (16 mg, 0.15 mmol) and NaI (19 mg,0.124 mmol) in DMF (0.25 mL) affording4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(TRANS, E135, 12 mg, y=20%). NMR: ¹H NMR (CDCl₃) δ: 7.66 (d, 1H),7.38-7.50 (m, 2H), 7.22-7.33 (m, 1H), 7.09 (d, 1H), 6.76-6.84 (m, 2H),3.70 (s, 3H), 3.40 (m, 2H), 2.53-2.93 (m, 5H), 2.29-2.40 (m, 2H), 2.02(m, 2H), 1.48-1.69 (m, 1H), 1.16-1.34 (m, 3H). MS (m/z): 490.4 [MH]⁺.

Example 136:1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E136)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p15, CIS,Enantiomer 1, 25 mg, 0.096 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2-dihydropyridin-2-one(p161, 30 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.2 mL) affording1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E136, 40 mg, y=82%). NMR: ¹H NMR (Acetone-d₆) δ:7.72-7.77 (m, 1H), 7.59-7.65 (m, 2H), 7.36-7.43 (m, 2H), 6.68-6.73 (m,1H), 6.56-6.63 (m, 1H), 3.76 (s, 3H), 3.51-3.58 (m, 3H), 3.15-3.35 (m,2H), 2.58 (br. s., 4H), 2.23-2.29 (m, 1H), 2.17 (br. s., 1H), 1.81-2.02(m, 5H), 1.29-1.35 (m, 1H), 1.20-1.26 (m, 1H). MS (m/z): 504.3 [MH]⁺.

Example 137:1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E137)

1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E136, 40 mg) was dissolved in MeOH and treated withHCl 2M in Et₂O (1.1 eq) to form the corresponding hydrochloride salt.Solvent was eliminated under reduced pressure; the solid was trituratedwith Et₂O and dried under high vacuum affording1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E137, 42 mg). MS (m/z): 504.3 [MH]⁺.

Example 138:4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E138)

The compound was prepared as in Example 1, reacting(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p24, CIS, 26 mg, 0.1 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2-dihydropyridin-2-one(p161, 33 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E138, 29 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ:7.72-7.81 (m, 1H), 7.45-7.54 (m, 2H), 7.30-7.45 (m, 1H), 6.68-6.76 (m,1H), 6.55-6.63 (m, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.19-3.37 (m, 2H),2.26-2.68 (m, 7H), 1.77-2.01 (m, 4H), 1.19-1.48 (m, 2H). MS (m/z): 522.4[MH]⁺.

Example 139:4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E139)

4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E138, 29 mg) was dissolved in MeOH and treated withHCl 2M in Et₂O (1.1 eq) to form the corresponding hydrochloride salt.Solvent was eliminated under reduced pressure; the solid was trituratedwith Et₂O and dried under high vacuum affording4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-onehydrochloride (CIS, Enantiomer 1, E139, 30.7 mg). MS (m/z): 522.3 [MH]⁺.

Example 140:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E140)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p13,TRANS, 50 mg, 0.207 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p162, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E140, 57 mg, y=58%). NMR: ¹H NMR (Acetone-d₆) δ: 8.68-8.73 (m,1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.62 (d, 2H), 7.45-7.51 (m, 1H), 7.35(d, 2H), 4.05 (s, 3H), 3.30-3.39 (m, 2H), 2.71-2.77 (m, 2H), 2.54-2.68(m, 5H), 2.23-2.31 (m, 1H), 1.93-2.02 (m, 2H), 1.61-1.71 (m, 1H),1.37-1.47 (m, 1H), 1.23-1.29 (m, 1H), 1.18-1.23 (m, 1H). MS (m/z): 474.4[MH]⁺.

Example 141:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, E141)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 35 mg, 0.15 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p162, 39 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(23 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.049 mL)was added and the reaction mixture was concentrated under vacuum. Thesolid so obtained was triturated with ether and dried under vacuum at45° C. O/N, affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, E141, 25 mg, y=30%). NMR: ¹H NMR (DMSO-d₆) δ:10.54-10.84 (m, 1H), 8.73 (d, 1H), 8.12 (d, 1H), 8.01 (m, 1H), 7.66 (d,2H), 7.54 (m, 1H), 7.44 (d, 2H), 3.92 (d, 3H), 3.65-3.75 (m, 1H),2.92-3.46 (m, 7H), 2.59-2.70 (m, 1H), 2.18-2.43 (m, 2H), 1.92-2.16 (m,3H), 1.25-1.53 (m, 2H). MS (m/z): 474.5 [MH]⁺.

Example 142:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E142)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p13,TRANS, 50 mg, 0.207 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E142, 58 mg, y=59%). NMR: ¹H NMR (Acetone-d₆) δ: 8.96 (d, 1H),8.73 (m, 1H), 8.15 (d, 1H), 7.63 (d, 2H), 7.54-7.60 (m, 1H), 7.35 (d,2H), 3.76 (s, 3H), 3.33 (m, 2H), 2.73-2.77 (m, 1H), 2.54-2.68 (m, 6H),2.24-2.31 (m, 1H), 1.97 (s, 2H), 1.62-1.72 (m, 1H), 1.38-1.49 (m, 1H),1.27 (m, 1H), 1.19-1.24 (m, 1H). MS (m/z): 474.4 [MH]⁺.

Example 143:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloride (CIS, E143)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 35 mg, 0.15 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 39 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(25 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.049 mL)was added and the reaction mixture was concentrated under vacuum. Thesolid so obtained was triturated with ether and dried under vacuum at45° C. O/N, affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloride (CIS, E143, 28 mg, y=34%). NMR: ¹H NMR (DMSO-d₆) δ:11.12-11.38 (m, 1H), 9.02 (d, 1H), 8.84 (m, 1H), 8.36 (d, 1H), 7.78 (m,1H), 7.65 (m, 2H), 7.45 (m, 2H), 3.60-3.72 (m, 4H), 2.89-3.46 (m, 7H),2.56-2.66 (m, 1H), 2.18-2.48 (m, 2H), 1.94-2.16 (m, 3H), 1.48 (s, 2H).MS (m/z): 474.5 [MH]⁺.

Example 144 and 145:(1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(CIS, Enantiomer 1, E144) and(1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(CIS, Enantiomer 2, E145)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptaneprepared in analogy with E143 (CIS, 56 mg) was separated into the singleenantiomers by preparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Mobile phase (Methanol + 0.1%isopropylamine) 27% Flow rate (ml/min) 45 ml/min DAD detection 220 nmLoop 500 μL Injection 14 mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(CIS, E144, 16.6 mg). Enantiomer 1: ret. time 6.3 min, 100% ee. MS(m/z): 474.4 [MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(CIS, E145, 15.8 mg). Enantiomer 2: ret. time 10.0 min, 100% ee. MS(m/z): 474.4 [MH]⁺.

Example 146:(1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 2, E146)

(1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(CIS, E145, 15.8 mg) was treated with 2.2 eq of HCl in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 2, E146, 13.8 mg). MS (m/z): 482.5[MH]⁺.

Example 147:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E147)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.193 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 57 mg, 0.212 mmol), Na₂CO₃ (25 mg, 0.23 mmol) and NaI (35 mg,0.23 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E147, 47 mg, y=49%). NMR: ¹H NMR (Acetone-d₆) δ: 8.96 (d, 1H),8.72-8.77 (m, 1H), 8.13-8.18 (m, 1H), 7.56-7.60 (m, 1H), 7.49 (d, 2H),7.32-7.38 (m, 1H), 3.73 (s, 3H), 3.17-3.36 (m, 2H), 2.44-2.71 (m, 5H),2.26-2.30 (m, 1H), 1.96-2.05 (m, 3H), 1.83-1.90 (m, 2H), 1.22-1.41 (m,2H). MS (m/z): 492.4 [MH]⁺.

Example 148 and 149:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E148) and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E149)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E147, 56 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 22% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 700 μL Injection 15.8mg/injection

affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E148, 12 mg). Enantiomer 1: ret. time 6.7 min, 100% ee. MS (m/z):492.4 [MH]⁺ and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E149, 12.4 mg). Enantiomer 2: ret. time 9.1 min, 99.8% ee. MS(m/z): 492.4 [MH]⁺.

Example 150:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E150)

(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E148, 12 mg) was treated with 2.2 eq of HCl in Et₂O affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 1, E150, 13 mg). MS (m/z): 492.4[MH]⁺.

Example 151:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 2, E151)

(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E149, 12.4 mg) was treated with 2.2 eq of HCl in Et₂O affording(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 2, E151, 13 mg). MS (m/z): 492.4[MH]⁺.

Example 152:(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E152)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (CIS, p29,50 mg, 0.24 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 71 mg, 0.26 mmol), Na₂CO₃ (31 mg, 0.28 mmol) and NaI (43 mg,0.288 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E152, 41 mg, y=39%). NMR: ¹H NMR (Acetone-d₆) δ: 8.94-8.99 (m,1H), 8.72-8.77 (m, 1H), 8.14-8.19 (m, 1H), 7.55-7.62 (m, 1H), 7.12-7.20(m, 1H), 6.90-7.04 (m, 2H), 3.74 (s, 3H), 3.26 (d, 2H), 2.74-2.78 (m,1H), 2.59-2.66 (m, 1H), 2.47-2.56 (m, 2H), 2.38 (d, 1H), 2.09-2.15 (m,1H), 1.95-2.02 (m, 3H), 1.82-1.92 (m, 2H), 1.20-1.25 (m, 1H), 1.12-1.19(m, 1H). MS (m/z): 442.4[MH]⁺.

Example 153 and 154:(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E153) and(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E154)

(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E152, 41 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 25% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 700 μL Injection 14mg/injection

affording(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E153, 13 mg). Enantiomer 1: ret. time 7.8 min, 100% ee. MS (m/z):442.3 [MH]⁺ and(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E154, 12.8 mg). Enantiomer 2: ret. time 11.6 min, 99.8% ee. MS(m/z): 442.4 [MH]⁺.

Example 155:(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E155)

(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E153, 13 mg) was treated with 2.2 eq of HCl in Et₂O affording(1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 1, E155, 15 mg). MS (m/z): 442.4[MH]⁺.

Example 156:(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 2, E156)

(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E154, 12.8 mg) was treated with 2.2 eq of HCl in Et₂O affording(1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 2, E156, 14.5 mg). MS (m/z): 442.3[MH]⁺.

Example 157:(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E157)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (CIS, p33, 50mg, 0.26 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 77 mg, 0.29 mmol), Na₂CO₃ (33 mg, 0.31 mmol) and NaI (47 mg, 0.31mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E157, 34 mg, y=31%). NMR: ¹H NMR (Acetone-d₆) δ: 8.97 (d, 1H),8.74 (m, 1H), 8.16 (m, 1H), 7.58 (m, 1H), 7.17-7.24 (m, 2H), 7.01-7.09(m, 2H), 3.72-3.76 (m, 3H), 3.18-3.32 (m, 2H), 2.62-2.78 (m, 2H), 2.52(m, 2H), 2.36-2.44 (m, 1H), 2.09-2.15 (m, 2H), 1.82-2.02 (m, 4H),1.06-1.16 (m, 2H). MS (m/z): 424.4 [MH]⁺.

Example 158 and 159:(1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E158) and(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E159)

(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E157, 34 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase (Methanol + 0.1%isopropylamine) 25% Flow rate (ml/min) 45 ml/min DAD detection 220 nmLoop 700 μL Injection 10.5 mg/injection

affording(1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E158, 10.7 mg). Enantiomer 1: ret. time 10.2 min, 100% ee. MS(m/z): 424.4 [MH]⁺ and(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E159, 10.8 mg). Enantiomer 2: ret. time 15.9 min, 99.8% ee. MS(m/z): 424.4 [MH]⁺.

Example 160:(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 2, E160)

(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E159, 13 mg) was treated with 2.2 eq of HCl in Et₂Oaffording(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 2, E160, 10 mg). MS (m/z): 424.5[MH]⁺.

Example 161:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E161)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS, p19, 50 mg, 0.289mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p163, 85 mg, 0.317 mmol), Na₂CO₃ (37 mg, 0.35 mmol) and NaI (53 mg,0.35 mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane(CIS, E161, 55 mg, y=47%). NMR: ¹H NMR (Acetone-d₆) δ: 8.94-9.00 (m,1H), 8.72-8.79 (m, 1H), 8.13-8.21 (m, 1H), 7.54-7.62 (m, 1H), 7.29 (s,2H), 7.19 (d, 3H), 3.74 (s, 3H), 3.20-3.36 (m, 3H), 2.52-3.00 (m, 5H),2.26-2.38 (m, 1H), 2.17 (d, 1H), 1.87-2.04 (m, 4H), 1.22 (d, 1H),1.12-1.19 (m, 1H). MS (m/z): 406.4 [MH]⁺.

Example 162:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E162)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p164, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E162, 61 mg, y=62%). NMR: ¹H NMR (Acetone-d₆) δ: 8.74-8.80 (m,2H), 7.75-7.80 (m, 2H), 7.63 (d, 2H), 7.36 (d, 2H), 3.81 (s, 3H), 3.35(m, 2H), 2.64 (br. s., 6H), 2.24-2.32 (m, 1H), 2.09-2.13 (m, 1H), 1.99(m, 2H), 1.62-1.75 (m, 1H), 1.38-1.50 (m, 1H), 1.27 (d, 1H), 1.22 (s,1H). MS (m/z): 474.4 [MH]⁺.

Example 163:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloride (CIS, E163)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 35 mg, 0.15 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p164, 39 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane(27 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (2 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.overnight, affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptanedihydrochloride (CIS, E163, 30 mg, y=30%). NMR: ¹H NMR (DMSO-d₆) δ:11.13-11.35 (m, 1H), 8.92 (d, 2H), 8.07 (d, 2H), 7.61-7.72 (m, 2H), 7.45(m, 2H), 3.73 (d, 3H), 3.61-3.70 (m, 1H), 3.35-3.45 (m, 1H), 3.23-3.35(m, 3H), 3.03-3.22 (m, 2H), 2.56-2.65 (m, 1H), 2.56-2.98 (m, 1H),2.36-2.49 (m, 1H), 1.94-2.34 (m, 4H), 1.25-1.51 (m, 2H). MS (m/z): 474.4[MH]⁺.

Example 164:(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E164)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p22, 30 mg, 0.12 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine(p164, 35 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(TRANS, E164, 35.5 mg, y=56%). NMR: ¹H NMR (Acetone-d₆) δ: 8.77 (d, 2H),7.73-7.79 (m, 2H), 7.45-7.54 (m, 2H), 7.27-7.34 (m, 1H), 3.82 (s, 3H),3.36 (m, 2H), 2.59-2.78 (m., 6H), 2.33 (m, 1H), 1.95-2.04 (m, 2H),1.63-1.72 (m, 1H), 1.23-1.46 (m, 3H). MS (m/z): 492.4 [MH]⁺.

Example 165:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E165)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 40 mg, 0.17 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine(p165, 48 mg, 0.17 mmol), Na₂CO₃ (22 mg, 0.2 mmol) and NaI (25 mg, 0.17mmol) in DMF (0.25 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E165, 24 mg, y=29%). NMR: ¹H NMR (CDCl₃) δ: 8.68 (m, 1H), 7.66 (m,1H), 7.54 (d, 2H), 7.26-7.33 (m, 1H), 7.22 (d, 2H), 3.27-3.43 (m, 5H),2.79-2.88 (m, 1H), 2.63-2.72 (m, 1H), 2.57 (s, 2H), 2.50 (s, 3H),2.41-2.47 (m, 1H), 2.16 (d, 2H), 1.90-2.07 (m, 4H), 1.74-1.78 (m, 1H),1.16-1.26 (m, 2H). MS (m/z): 488.5 [MH]⁺.

Example 166:(1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E166)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg,3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine(p165, 35 mg, 0.12 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording (1R,3S or1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(11 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (2.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.overnight, affording(1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E166, 12 mg, y=18%). NMR: ¹H NMR(DMSO-d₆) δ: 10.72-10.99 (m, 1H), 8.70-8.77 (m, 1H), 8.04-8.14 (m, 1H),7.66 (d, 2H), 7.56-7.62 (m, 1H), 7.45 (d, 2H), 3.63-3.73 (m, 2H),3.36-3.48 (m, 4H), 3.07-3.34 (m, 6H), 2.91-3.01 (m, 1H), 2.59-2.71 (m,1H), 2.17-2.44 (m, 2H), 2.09 (br. s., 3H), 1.36-1.53 (m, 2H), 1.21-1.35(m, 1H). MS (m/z): 488.4 [MH]⁺.

Example 167:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E167)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p40, 30 mg, 0.124 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl)}-2-methylpyridine(p165, 35 mg, 0.124 mmol), Na₂CO₃ (16 mg, 0.15 mmol) and NaI (19 mg,0.124 mmol) in DMF (0.25 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E167, 14.5 mg, y=24%). NMR: ¹H NMR (CDCl₃) δ: 8.69 (s, 1H),7.66-7.72 (m, 2H), 7.45-7.52 (m, 1H), 7.32 (s, 2H), 7.09-7.14 (m, 1H),3.41 (s, 5H), 2.85-2.93 (m, 1H), 2.62-2.76 (m, 4H), 2.50-2.54 (m, 3H),2.34-2.43 (m, 2H), 2.03-2.12 (m, 2H), 1.58 (br. s., 1H), 1.23-1.35 (m,4H). MS (m/z): 488.4 [MH]⁺.

Example 168:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (TRANS, E168)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E167, 14.5 mg) was dissolved in Et₂O and treated with 2.2 eq ofHCl in Et₂O affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloric salt (TRANS, E168, 13.7 mg). MS (m/z): 488.4 [MH]⁺.

Example 169:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E169)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 40 mg, 0.17 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine(p166, 48 mg, 0.17 mmol), Na₂CO₃ (22 mg, 0.2 mmol) and NaI (25 mg, 0.17mmol) in DMF (0.25 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E169, 35 mg, y=42%). NMR: ¹H NMR (CDCl₃) δ: 8.77 (d, 1H), 7.91 (m,1H), 7.54 (d, 2H), 7.33 (d, 1H), 7.21 (d, 2H), 3.59 (s, 3H), 3.23-3.37(m, 2H), 2.79-2.89 (m, 1H), 2.67 (s, 4H), 2.57 (s, 2H), 2.42-2.48 (m,1H), 2.11-2.19 (m, 2H), 1.90-2.07 (m, 5H), 1.21 (s, 2H). MS (m/z): 488.5[MH]⁺.

Example 170:(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E170)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol)2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-3-methylpyridine(p167, 31 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(28.8 mg).

The latter was dissolved in DCM/Et₂O then 2N HCl/ether (2.2 eq) wasadded and the reaction mixture was concentrated under vacuum affording(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E170, 30.9 mg, y=55%). NMR: ¹H NMR(DMSO-d₆) δ: 9.84-10.16 (m, 3H), 8.54-8.60 (m, 1H), 7.84-7.91 (m, 1H),7.66 (d, 2H), 7.45 (d, 3H), 3.67-3.77 (m, 2H), 3.60 (s, 3H), 3.39 (br.s., 2H), 3.22 (d, 3H), 2.45 (s, 3H), 2.36-2.43 (m, 1H), 2.18-2.30 (m,2H), 1.95-2.15 (m, 3H), 1.26-1.52 (m, 3H). MS (m/z): 488.4 [MH]⁺.

Example 171:(1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer1, E171)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2,6-dimethylpyridine(p168, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.123 mmol) and NaI (19 mg,0.123 mmol) in DMF (0.15 mL) affording(1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E171, 36 mg, y=71%). NMR: ¹H NMR (Acetone-d₆) δ:7.66-7.70 (m, 1H), 7.59-7.64 (m, 2H), 7.38-7.44 (m, 2H), 7.21-7.26 (m,1H), 3.45 (s, 3H), 3.18-3.36 (m, 3H), 2.82-2.90 (m, 1H), 2.57-2.74 (m,3H), 2.55 (s, 3H), 2.39 (s, 3H), 2.25-2.34 (m, 1H), 2.09-2.15 (m, 1H),1.98-2.05 (m, 3H), 1.89-1.97 (m, 2H), 1.21-1.38 (m, 2H). MS (m/z): 502.4[MH]⁺.

Example 172:(1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E172)

(1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E171, 36 mg) was dissolved in Et₂O and treated with2.2 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affording(1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, E172, 40.8 mg). MS (m/z): 502.4 [MH]⁺.

Example 173:(1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E173)

A sealed vial containing a mixture of(1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p258, 25 mg, 0.079 mmol),5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (p85, 17 mg,0.083 mmol), Na₂CO₃ (10 mg, 0.095 mmol) and NaI (12 mg, 0.079 mmol) andDMF (0.2 mL) was shaken O/N at 60° C. in a PLS apparatus. The mixturewas diluted with DCM, the organic phase was washed twice with water,dried over sodium sulfate and the solvent removed under reducedpressure. The crude material was purified by FC on silica gel (elutingwith DCM/MeOH from 100/0 to 90/10) to give(1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E173, 24.5 mg, y=63%). NMR: ¹H NMR (DMSO-d₆) δ:8.47-8.51 (m, 1H), 8.21-8.28 (m, 1H), 7.57-7.64 (m, 3H), 7.34 (d, 2H),3.46 (d, 3H), 3.10-3.21 (m, 2H), 2.74 (br. s., 1H), 2.38-2.56 (m, 3H),2.24 (br. s., 1H), 1.72-2.05 (m, 6H), 1.25-1.33 (m, 1H), 1.14-1.25 (m,1H). MS (m/z): 492.4 [MH]⁺.

Example 174:(1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E174)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol)3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-(trifluoromethyl)pyridine(p169, 44 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(40 mg).

The latter was dissolved in DCM then 2N HCl/ether (2.2 eq) was added andthe reaction mixture was concentrated under vacuum. The solid soobtained was triturated with ether and dried under vacuum at 45° C. O/Naffording(1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl)}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E174, 41 mg, y=55%). NMR: ¹H NMR(DMSO-d₆) δ: 10.24-10.57 (m, 1H), 8.98 (d, 1H), 8.25 (d, 1H), 7.95 (m,1H), 7.66 (d, 2H), 7.44 (m, 2H), 3.65-3.77 (m, 1H), 3.41-3.48 (m, 1H),3.35 (br. s., 3H), 3.23 (d, 6H), 2.63-3.04 (m, 1H), 2.20-2.45 (m, 2H),1.92-2.16 (m, 3H), 1.27-1.53 (m, 2H). MS (m/z): 542.4 [MH]⁺.

Example 175:(1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E175)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol)3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methoxypyridine(p170, 39 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E175, 33 mg, y=52%). NMR: ¹H NMR (CDCl3) δ:8.32-8.39 (m, 1H), 7.84-7.92 (m, 1H), 7.55 (d, 2H), 7.21-7.27 (m, 2H),7.04-7.10 (m, 1H), 4.00 (s, 3H), 3.43 (s, 3H), 3.29 (m, 2H), 2.98-3.12(m, 1H), 2.59-2.98 (m, 4H), 2.25-2.38 (m, 1H), 2.18-2.25 (m, 1H), 2.06(d, 4H), 1.28 (d, 2H). MS (m/z): 504.4 [MH]⁺.

Example 176:(1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E176)

(1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E175, 28 mg) was dissolved in DCM and treated with2.2 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affording(1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, E176, 30 mg). MS (m/z): 504.4 [MH]⁺.

Example 177:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitriledihydrochloride (CIS, Enantiomer 1, E177)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.10 mmol)5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carbonitrile(p171, 30 mg, 0.10 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (15 mg, 0.10mmol) in DMF (0.15 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile(15 mg).

The latter was dissolved in DCM then 2N HCl/ether (2.1 eq) was added andthe reaction mixture was concentrated under vacuum. The solid soobtained was triturated with ether and dried under vacuum at 45° C. O/Naffording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitriledihydrochloride (CIS, Enantiomer 1, E177, 17 mg, y=30%). NMR: ¹H NMR(DMSO-d₆) δ: 10.41-10.70 (m, 1H), 9.11 (s, 1H), 8.42 (s, 1H), 8.27 (d,1H), 7.66 (d, 2H), 7.38-7.49 (m, 2H), 3.67 (d, 3H), 3.06-3.47 (m, 7H),2.61-3.01 (m, 1H), 2.45-2.50 (m, 1H), 2.20-2.44 (m, 2H), 1.92-2.15 (m,3H), 1.26-1.53 (m, 2H). MS (m/z): 499.5 [MH]⁺.

Example 178:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile(CIS, Enantiomer 1, E178)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 80 mg, 0.33 mmol)4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carbonitrile(p172, 98 mg, 0.33 mmol), Na₂CO₃ (42 mg, 0.4 mmol) and NaI (49 mg, 0.33mmol) in DMF (0.5 mL) affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile(CIS, Enantiomer 1, E178, 53 mg, y=32%). NMR: ¹H NMR (CDCl3) δ:8.88-8.94 (m, 1H), 8.05-8.08 (m, 1H), 7.88-7.92 (m, 1H), 7.52-7.60 (m,2H), 7.22-7.27 (m, 2H), 3.73 (s, 3H), 3.31-3.40 (m, 2H), 3.03-3.16 (m,1H), 2.64-3.01 (m, 4H), 2.30-2.42 (m, 1H), 2.21-2.27 (m, 1H), 2.02-2.20(m, 4H), 1.30 (d, 2H). MS (m/z): 499.4 [MH]⁺.

Example 179:5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, E179)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.21 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p173, 72 mg, 0.231 mmol), Na₂CO₃ (38 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) in DMF (0.236 mL) affording5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, E179, 47.6 mg, y=43%). NMR: ¹H NMR (Acetone-d₆) δ: 8.99-9.01 (m,1H), 8.36 (d, 1H), 8.29 (d, 1H), 7.95-8.04 (m, 1H), 7.62 (d, 2H),7.32-7.39 (m, 2H), 6.87-6.95 (m, 1H), 3.81 (s, 3H), 3.30-3.38 (m, 2H),2.72-2.75 (m, 1H), 2.54-2.66 (m, 5H), 2.23-2.30 (m, 1H), 1.92-2.02 (m,2H), 1.61-1.70 (m, 1H), 1.40-1.48 (m, 1H), 1.23-1.29 (m, 1H), 1.17-1.23(m, 1H). MS (m/z): 517.4 [MH]⁺.

Example 180 and 181: 5-[4-methyl-5-({3-[(1S,3S or1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, Enantiomer 1, E180) and 5-[4-methyl-5-({3-[(1R,3R or1S,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, Enantiomer 2, E181)

5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, E179, 47.6 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 10/90% v/v Flowrate (ml/min) 15 ml/min DAD detection 220 nm Loop 1000 μL Injection 11mg/injectionaffording 5-[4-methyl-5-({3-[(1S,3S or1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, E180, 15.6 mg). Enantiomer 1: ret. time 4.8 min, 100% ee. MS(m/z): 517.3 [MH]⁺ and 5-[4-methyl-5-({3-[(1R,3R or1S,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(TRANS, E181, 14.4 mg). Enantiomer 2: ret. time 5.6 min, 99.8% ee. MS(m/z): 517.3 [MH]⁺.

Example 182:5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, E182)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.116 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p173, 41 mg, 0.13 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (21 mg, 0.14mmol) in DMF (0.2 mL) affording5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, E182, 23 mg, y=38%). NMR: ¹H NMR (CDCl3) δ: 8.90-8.96 (m, 1H),8.36-8.41 (m, 1H), 8.15-8.20 (m, 1H), 7.81-7.91 (m, 1H), 7.52-7.59 (m,2H), 7.20-7.26 (m, 2H), 5.64-5.74 (m, 1H), 3.66 (s, 3H), 3.26-3.41 (m,2H), 2.84-2.95 (m, 1H), 2.74 (d, 1H), 2.63 (m, 2H), 2.50 (d, 1H),2.14-2.26 (m, 2H), 1.92-2.11 (m, 4H), 1.19-1.33 (m, 2H). MS (m/z): 517.5[MH]⁺.

Example 183:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E183)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p173, 33 mg, 0.106 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.1 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E183, 13 mg, y=26%). NMR: ¹H NMR (Acetone-d₆) δ:8.97-9.02 (m, 1H), 8.36 (d, 1H), 8.25-8.31 (m, 1H), 7.95-8.07 (m, 1H),7.62 (d, 2H), 7.39 (d, 2H), 6.85-6.98 (m, 1H), 3.73-3.81 (m, 3H),3.18-3.36 (m, 2H), 2.39-2.71 (m, 5H), 2.24 (d, 1H), 2.10-2.17 (m, 1H),1.79-2.04 (m, 4H), 1.30 (br. s., 1H), 1.23 (d, 1H). MS (m/z): 517.5[MH]⁺.

Example 184:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidedihydrochloride (CIS, Enantiomer 1, E184)

5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E183, 13 mg) was dissolved in DCM and treated with2.2 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidedihydrochloric salt (CIS, Enantiomer 1, E184, 14 mg). MS (m/z): 517.4[MH]⁺.

Example 185:5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E185)

The compound was prepared as in Example 1, reacting(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p24, 25 mg, 0.096 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p173, 34 mg, 0.11 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.108 mL) affording5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E185, 26.5 mg, y=52%). NMR: ¹H NMR (Acetone-d₆) δ:8.96-9.02 (m, 1H), 8.33-8.39 (m, 1H), 8.26-8.31 (m, 1H), 7.97-8.06 (m,1H), 7.45-7.51 (m, 2H), 7.32-7.39 (m, 1H), 6.84-6.97 (m, 1H), 3.78 (s,3H), 3.19-3.33 (m, 2H), 2.77 (br. s., 6H), 2.24-2.33 (m, 1H), 2.03 (br.s., 2H), 1.82-1.94 (m, 2H), 1.35-1.42 (m, 1H), 1.22-1.29 (m, 1H). MS(m/z): 535.4 [MH]⁺.

Example 186:5-[5-({3-[(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 2, E186)

The compound was prepared as in Example 1, reacting(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, p25, 25 mg, 0.096 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p173, 34 mg, 0.11 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.108 mL) affording5-[5-({3-[(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 2, E186, 19.9 mg, y=38%). NMR: ¹H NMR (Acetone-d₆) δ:8.96-9.02 (m, 1H), 8.33-8.39 (m, 1H), 8.26-8.31 (m, 1H), 7.97-8.06 (m,1H), 7.45-7.51 (m, 2H), 7.32-7.39 (m, 1H), 6.84-6.97 (m, 1H), 3.78 (s,3H), 3.19-3.33 (m, 2H), 2.77 (br. s., 6H), 2.24-2.33 (m, 1H), 2.03 (br.s., 2H), 1.82-1.94 (m, 2H), 1.35-1.42 (m, 1H), 1.22-1.29 (m, 1H). MS(m/z): 535.4 [MH]⁺.

Example 187:6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E187)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide(p234, 37 mg, 0.11 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.108 mL) affording6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E187, 27 mg, y=51%). NMR: ¹H NMR (DMSO-d₆) δ:8.10-8.16 (m, 1H), 8.01 (d, 2H), 7.73-7.78 (m, 1H), 7.59 (s, 2H),7.29-7.36 (m, 2H), 3.37 (s, 3H), 3.10-3.20 (m, 2H), 2.69-2.74 (m, 1H),2.36-2.54 (m, 7H), 2.17-2.24 (br. s., 1H), 1.82-1.98 (m, 3H), 1.71-1.81(m, 2H), 1.23-1.31 (m, 1H), 1.16 (d, 1H). MS (m/z): 531.4 [MH]⁺.

Example 188:6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylicacid formate (CIS, Enantiomer 1, E188)

(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.096 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxylicacid (p235, 300 mg, assumed 0.9 mmol), Na₂CO₃ (120 mg, 1.15 mmol) andNaI (17 mg, 0.115 mmol) were dissolved in DMF (0.4 mL) and heated at 60°C. O/N. The mixture was charged on C18 and it was purified by FC on C18cartridge (eluent water+0.1% FA to 60% water+0.1% FA 40% MeOH+0.1%)affording6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylicacid formate (CIS, Enantiomer 1, E188, 12 mg, y=18%) as white solid.NMR: ¹H NMR (Acetone-d₆) δ: 8.15 (s, 1H), 8.10-8.13 (m, 1H), 7.61 (s,2H), 7.36-7.43 (m, 2H), 3.54 (s, 3H), 3.18-3.37 (m, 4H), 2.72 (br. s.,1H), 2.51-2.64 (m, 6H), 2.25-2.31 (m, 1H), 2.09 (br. s., 2H), 1.93-2.02(m, 2H), 1.86-1.90 (m, 1H), 1.28-1.35 (m, 1H), 1.21-1.26 (m, 1H). MS(m/z): 532.4 [MH]⁺.

Example 189:6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol3-yl]pyridine-3-carboxamide dihydrochloride (CIS, Enantiomer 1, E189)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide(p174, 43 mg, 0.14 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide(27.5 mg).

The latter was dissolved in DCM then 2N HCl/ether (2.2 eq) was added andthe reaction mixture was concentrated under vacuum. The solid soobtained was triturated with ether and dried under vacuum at 45° C.overnight affording6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamidedihydrochloride (CIS, Enantiomer 1, E189, 31 mg, y=44%). NMR: ¹H NMR(DMSO-d₆) δ: 10.66-10.87 (m, 1H), 9.15 (d, 1H), 8.38-8.44 (m, 1H), 8.30(br. s., 1H), 8.22 (d, 1H), 7.72 (br. s., 1H), 7.67 (d, 2H), 7.45 (d,2H), 3.95 (d, 3H), 3.66-3.75 (m, 1H), 2.94-3.46 (m, 7H), 1.96-2.69 (m,5H), 1.28-1.53 (m, 2H). MS (m/z): 517.4 [MH]⁺.

Example 190:6-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide(CIS, Enantiomer 1, E190)

The compound was prepared as in Example 1, reacting(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p24, 26 mg, 0.1 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide(p174, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording6-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide(CIS, Enantiomer 1, E190, 20.5 mg, y=38%). NMR: ¹H NMR (DMSO-d₆) δ:9.08-9.18 (m, 1H), 8.35-8.44 (m, 1H), 8.24-8.29 (m, 1H), 8.19-8.24 (m,1H), 7.68-7.74 (m, 1H), 7.58-7.64 (m, 1H), 7.45-7.50 (m, 1H), 7.25-7.32(m, 1H), 3.92 (s, 3H), 3.10-3.22 (m, 2H), 2.69-2.78 (m, 1H), 2.35-2.43(m, 4H), 2.21 (m, 1H), 1.93 (m, 2H), 1.84 (d, 1H), 1.75 (m, 2H), 1.35(m, 1H), 1.20 (m, 1H). MS (m/z): 535.3 [MH]⁺.

Example 191:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E191)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol)4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p175, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E191, 34.7 mg, y=67%). NMR: ¹H NMR (Acetone-d₆) δ:8.80 (m, 1H), 8.49 (m, 1H), 7.99-8.04 (m, 1H), 7.97 (m, 1H), 7.61 (d,2H), 7.38 (d, 2H), 6.82-6.96 (m, 1H), 3.82 (s, 3H), 3.18-3.34 (m, 2H),2.70-2.75 (m, 1H), 2.58-2.66 (m, 1H), 2.43-2.57 (m, 3H), 2.20-2.27 (m,1H), 1.81-2.03 (m, 5H), 1.26-1.31 (m, 1H), 1.21 (m, 1H). MS (m/z): 517.4[MH]⁺.

Example 192:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide(CIS, Enantiomer 1, E192)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol)5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide(p236, 36 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide(CIS, Enantiomer 1, E192, 31 mg, y=60%). NMR: ¹H NMR (Acetone-d₆) δ:9.22 (d, 1H), 9.07 (d, 1H), 8.56 (s, 1H), 7.74-7.88 (m, 1H), 7.60 (s,2H), 7.39 (s, 2H), 6.93-7.06 (m, 1H), 3.76 (s, 3H), 3.16-3.34 (m, 2H),2.70-2.76 (m, 1H), 2.58-2.67 (m, 1H), 2.43-2.56 (m, 3H), 2.18-2.27 (m,1H), 2.08-2.11 (m, 1H), 1.92-2.03 (m, 2H), 1.81-1.92 (m, 2H), 1.25-1.32(m, 1H), 1.17-1.24 (m, 1H). MS (m/z): 517.3 [MH]⁺.

Example 193:6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E193)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide(p176, 32 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.115 mmol) and NaI (18 mg,0.115 mmol) in DMF (0.1 mL) affording6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E193, 25.5 mg, y=51%). NMR: ¹H NMR (DMSO-d₆) δ:8.23-8.29 (m, 1H), 8.11-8.22 (m, 2H), 7.96-8.01 (m, 1H), 7.80-7.88 (m,1H), 7.58-7.64 (m, 2H), 7.30-7.35 (m, 2H), 3.93 (s, 3H), 3.11-3.23 (m,2H), 2.66-2.76 (m, 1H), 2.37-2.49 (m, 4H), 2.21 (m, 1H), 1.83-2.01 (m,3H), 1.77 (m, 2H), 1.27 (m, 1H), 1.18 (m, 1H). MS (m/z): 517.4 [MH]⁺.

Example 194:N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E194)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-N-methylpyridine-2-carboxamide(p177, 33 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.115 mmol) and NaI (18 mg,0.115 mmol) in DMF (0.2 mL) affordingN-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E194, 33 mg, y=64%). NMR: ¹H NMR (Acetone-d₆) δ:8.30-8.36 (m, 1H), 8.16-8.29 (m, 3H), 7.60-7.65 (m, 2H), 7.37-7.43 (m,2H), 4.02 (s, 3H), 3.24-3.38 (m, 2H), 3 (d, 3H), 2.51-2.71 (m, 4H),2.13-2.33 (m, 2H), 1.85-2.03 (m, 5H), 1.28-1.36 (m, 1H), 1.20-1.28 (m,1H). MS (m/z): 531.4 [MH]⁺.

Example 195:N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloride (CIS, Enantiomer 1, E195)

N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E194, 33 mg) was dissolved in MeOH and treated with1.1 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affordingN-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloric salt (CIS, Enantiomer 1, E195, 34.6 mg). MS (m/z): 531.4[MH]⁺.

Example 196:N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E196)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-N,N-dimethylpyridine-2-carboxamide(p178, 34 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.115 mmol) and NaI (18 mg,0.115 mmol) in DMF (0.2 mL) affordingN,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E196, 33 mg, y=63%). NMR: ¹H NMR (Acetone-d₆) δ:8.27-8.32 (m, 1H), 8.07-8.13 (m, 1H), 7.65-7.70 (m, 1H), 7.60-7.65 (m,2H), 7.36-7.42 (m, 2H), 4.03 (s, 3H), 3.20-3.36 (m, 2H), 3.12 (d, 6H),2.72-2.75 (m, 1H), 2.64 (d, 1H), 2.52 (br. s., 3H), 2.21-2.28 (m, 1H),1.94-2.04 (m, 3H), 1.82-1.94 (m, 2H), 1.30 (m, 1H), 1.22 (m, 1H). MS(m/z): 545.3 [MH]⁺.

Example 197:N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloride (CIS, Enantiomer 1, E197)

N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E196, 33 mg) was dissolved in MeOH and treated with1.1 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affordingN,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloric salt (CIS, Enantiomer 1, E197, 35.5 mg). MS (m/z): 545.4[MH]⁺.

Example 198:5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E198)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol)6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-5-methylpyridine-2-carboxamide(p179, 33 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.115 mmol) and NaI (18 mg,0.115 mmol) in DMF (0.2 mL) affording5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E198, 40 mg, y=78%). NMR: ¹H NMR (DMSO-d₆) δ:8.00-8.11 (m, 3H), 7.58-7.72 (m, 3H), 7.30-7.40 (m, 2H), 3.65 (s, 3H),3.15-3.26 (m, 3H), 2.54 (s, 3H), 2.41-2.49 (m, 2H), 1.75-2.29 (m, 8H),1.15-1.38 (m, 2H). MS (m/z): 531.3 [MH]⁺.

Example 199:5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloride (CIS, Enantiomer 1, E199)

5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide(CIS, Enantiomer 1, E198, 40 mg) was dissolved in MeOH and treated with1.1 eq of HCl in Et₂O. The solid so obtained was triturated with etherand dried under vacuum affording5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamidehydrochloric salt (CIS, Enantiomer 1, E199, 38 mg). MS (m/z): 531.3[MH]⁺.

Example 200:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E200)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.21 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine(p180, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.25 mmol) and NaI (37 mg,0.25 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E200, 46 mg, y=47%). NMR: ¹H NMR (Acetone-d₆) δ: 9.65 (m, 1H),9.40 (m, 1H), 8.05 (m, 1H), 7.64 (d, 2H), 7.36 (d, 2H), 3.90 (s, 3H),3.38 (m, 2H), 2.56-2.67 (m, 5H), 2.25-2.31 (m, 1H), 2.09-2.13 (m, 1H),1.94-2.03 (m, 2H), 1.63-1.72 (m, 1H), 1.39-1.48 (m, 1H), 1.25-1.30 (m,1H), 1.20-1.24 (m, 1H). MS (m/z): 475.4 [MH]⁺.

Example 201:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E201)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.124 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine(p180, 33 mg, 0.12 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (21 mg, 0.14mmol) in DMF (0.1 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E201, 37 mg, y=63%). NMR: ¹H NMR (Acetone-d₆) δ: 9.60-9.66 (m,1H), 9.37-9.42 (m, 1H), 8.02-8.08 (m, 1H), 7.60-7.66 (m, 2H), 7.36-7.43(m, 2H), 3.86 (s, 3H), 3.21-3.36 (m, 2H), 2.45-2.73 (m, 4H), 2.21-2.27(m, 1H), 2.08-2.15 (m, 1H), 1.83-2.03 (m, 5H), 1.19-1.33 (m, 2H). MS(m/z): 475.4 [MH]⁺.

Example 202 and 203:(1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E202) and(1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E203)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E201, 37 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 60/40% v/v Flow rate (ml/min) 17 ml/min DADdetection 220 nm Loop 1000 μL Injection 25 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E202, 11 mg). Enantiomer 1: ret. time 8.5 min, 100% ee. MS (m/z):475.3 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E203, 11.8 mg). Enantiomer 2: ret. time 10.3 min, 100% ee. MS(m/z): 475.5 [MH]⁺.

Example 204:(1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E204)

(1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E202, 11 mg) was treated with 1.1 eq of HCl in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E204, 11.9 mg). MS (m/z): 475.4[MH]⁺.

Example 205:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E205)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.21 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine(p181, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.25 mmol) and NaI (37 mg,0.25 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E205, 38 mg, y=39%). NMR: ¹H NMR (Acetone-d₆) δ: 9.27-9.36 (m,1H), 8.40 (d, 1H), 7.89 (d, 1H), 7.63 (d, 2H), 7.36 (d, 2H), 4.13 (s,3H), 3.33-3.49 (m, 2H), 2.74-2.79 (m, 2H), 2.56-2.68 (m, 4H), 2.24-2.31(m, 1H), 2.10-2.13 (m, 1H), 2.09-2.13 (m, 2H), 1.95-2.04 (m, 2H),1.62-1.71 (m, 1H), 1.39-1.49 (m, 1H), 1.25-1.30 (m, 1H), 1.18-1.24 (m,1H). MS (m/z): 475.4 [MH]⁺.

Example 206:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E206)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.124 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine(p181, 33 mg, 0.12 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (21 mg, 0.14mmol) in DMF (0.1 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E206, 34 mg, y=62%). NMR: ¹H NMR (Acetone-d₆) δ: 9.28-9.34 (m,1H), 8.37-8.44 (m, 1H), 7.84-7.91 (m, 1H), 7.59-7.66 (m, 2H), 7.37-7.45(m, 2H), 4.09 (s, 3H), 3.25-3.41 (m, 2H), 2.52-2.95 (m., 6H), 2.24-2.32(m, 1H), 1.87-2.04 (m, 4H), 1.20-1.38 (m, 2H). MS (m/z): 475.4 [MH]⁺.

Example 207:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E207)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.21 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrimidine(p182, 62.3 mg, 0.231 mmol), Na₂CO₃ (27 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) in DMF (0.22 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E207, 21 mg, y=19%). NMR: ¹H NMR (Acetone-d₆) δ: 9.28 (d, 1H),8.95 (d, 1H), 8.23 (m, 1H), 7.63 (d, 2H), 7.31-7.45 (m, 2H), 4.09 (s,3H), 3.34-3.47 (m, 2H), 2.56-2.75 (m, 4H), 2.26-2.39 (m, 1H), 1.97-2.05(m, 3H), 1.63-1.80 (m, 1H), 1.40-1.55 (m, 1H), 1.19-1.37 (m, 3H). MS(m/z): 475.5 [MH]⁺.

Example 208 and 209: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1, E208) and (1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 2, E209)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E207, 21 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 35/65% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 1000 μL Injection 18 mg/injection

affording (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E208, 5.4 mg). Enantiomer 1: ret. time 12.3 min, 100% ee. MS(m/z): 475.0 [MH]⁺ and (1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E209, 8.3 mg). Enantiomer 2: ret. time 16.3 min, 100% ee. MS(m/z): 475.0 [MH]⁺.

Example 210: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, Enantiomer 1, E210)

(1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E208, 5.4 mg) was treated with 1.2 eq of HCl in Et₂O affording(1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E210, 5 mg). MS (m/z): 475.0[MH]⁺.

Example 211: (1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, Enantiomer 2, E211)

(1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E209, 8.3 mg) was treated with 1.2 eq of HCl in Et₂O affording(1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E211, 2.5 mg). MS (m/z): 475.0[MH]⁺.

Example 212:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E212)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.21 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrimidine(p182, 62.3 mg, 0.231 mmol), Na₂CO₃ (27 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) in DMF (0.22 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E212, 57.2 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ: 9.27-9.31 (m,1H), 8.92-8.99 (m, 1H), 8.22-8.26 (m, 1H), 7.59-7.65 (m, 2H), 7.36-7.42(m, 2H), 4.07 (s, 3H), 3.22-3.39 (m, 2H), 2.71-2.76 (m, 2H), 2.59-2.68(m, 1H), 2.46-2.56 (m, 3H), 2.21-2.27 (m, 1H), 1.83-2.03 (m, 4H),1.26-1.32 (m, 1H), 1.22 (m, 1H). MS (m/z): 475.1 [MH]⁺.

Example 213:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E213)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.19 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrimidine(p182, 56.4 mg, 0.209 mmol), Na₂CO₃ (24 mg, 0.228 mmol) and NaI (34 mg,0.228 mmol) in DMF (0.22 mL) affording(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E213, 11.8 mg, y=12%). NMR: ¹H NMR (Acetone-d₆) δ: 9.27-9.32 (m,1H), 8.93-8.98 (m, 1H), 8.20-8.26 (m, 1H), 7.45-7.53 (m, 2H), 7.29-7.38(m, 1H), 4.07 (s, 3H), 3.24-3.45 (m, 2H), 2.44-2.67 (m, 5H), 2.25-2.35(m, 1H), 1.98-2.05 (m, 3H), 1.83-1.95 (m, 2H), 1.35-1.41 (m, 1H),1.23-1.29 (m, 1H). MS (m/z): 475.1 [MH]⁺.

Example 214:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E214)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.21 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine(p183, 62.3 mg, 0.231 mmol), Na₂CO₃ (27 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) in DMF (0.22 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E214, 24.5 mg, y=25%). NMR: ¹H NMR (Acetone-d₆) δ: 9.38 (d, 1H),8.72 (m, 2H), 7.63 (d, 2H), 7.33-7.52 (m, 2H), 4.02 (s, 3H), 3.40-3.50(m, 2H), 2.89-3.15 (m, 3H), 2.31-2.47 (m, 1H), 2.11-2.19 (m, 1H), 2.02(br. s., 1H), 1.72-1.86 (m, 2H), 1.43-1.65 (m, 2H), 1.25-1.41 (m, 3H).MS (m/z): 475.1 [MH]⁺.

Example 215 and 216: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 1, E215) and (1R,3R or1S,R3)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, Enantiomer 2, E216)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E214, 24.5 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 40/60% v/v Flow rate (ml/min) 14 ml/min DADdetection 220 nm Loop 1000 μL Injection 11.5 mg/injection

affording (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E215, 8.5 mg). Enantiomer 1: ret. time 11.7 min, 100% ee. MS(m/z): 475.1 [MH]⁺ and (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E216, 8.5 mg). Enantiomer 2: ret. time 16.0 min, 100% ee. MS(m/z): 475.1 [MH]⁺.

Example 217:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E217)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 50 mg, 0.21 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine(p183, 62.3 mg, 0.231 mmol), Na₂CO₃ (27 mg, 0.252 mmol) and NaI (38 mg,0.252 mmol) in DMF (0.22 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E217, 56.3 mg, y=54%). NMR: ¹H NMR (Acetone-d₆) δ: 9.39 (d, 1H),8.69-8.76 (m, 2H), 7.62 (d, 2H), 7.39 (d, 2H), 4.00 (s, 3H), 3.21-3.38(m, 2H), 2.72-2.77 (m, 2H), 2.60-2.68 (m, 1H), 2.47-2.57 (m, 3H),2.21-2.28 (m, 1H), 1.93-2.03 (m, 2H), 1.83-1.93 (m, 2H), 1.25-1.32 (m,1H), 1.19-1.24 (m, 1H). MS (m/z): 475.1 [MH]⁺.

Example 218 and 219:(1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E218) and(1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E219)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E217, 56.3 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 30% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 500 μL Injection 17mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E218, 21.8 mg). Enantiomer 1: ret. time 6.3 min, 100% ee. MS(m/z): 475.5 [MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E219, 11.4 mg). Enantiomer 2: ret. time 10.5 min, 89.2% ee. MS(m/z): 475.5 [MH]⁺.

Example 220:(1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 2, E220)

(1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E219, 11.4 mg) was dissolved in Et₂O/DCM and treatedwith 1.2 eq of HCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E220, 10.8 mg). MS (m/z): 475.1[MH]⁺.

Example 221:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E221)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.19 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine(p183, 56.4 mg, 0.209 mmol), Na₂CO₃ (24 mg, 0.228 mmol) and NaI (34 mg,0.228 mmol) in DMF (0.22 mL) affording(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane(CIS, E221, 52.7 mg, y=51%). NMR: ¹H NMR (Acetone-d₆) δ: 9.39 (d, 1H),8.70-8.77 (m, 2H), 7.47-7.52 (m, 2H), 7.34 (m, 1H), 4.00 (s, 3H),3.22-3.41 (m, 3H), 2.76 (br. s., 1H), 2.58-2.65 (m, 1H), 2.44-2.56 (m,2H), 2.24-2.30 (m, 1H), 1.96-2.05 (m, 3H), 1.83-1.94 (m, 2H), 1.35-1.41(m, 1H), 1.22-1.29 (m, 1H). MS (m/z): 493.1 [MH]⁺.

Example 222:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E222)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyrazine(p184, 37 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E222, 24.8 mg, y=41%). NMR: ¹H NMR (Acetone-d₆) δ: 9.17 (s, 1H),8.61 (s, 1H), 7.63 (d, 2H), 7.39-7.46 (m, 2H), 4.01 (s, 3H), 3.23-3.40(m, 2H), 2.57-2.94 (m, 9H), 2.30 (m, 1H), 1.90-2.04 (m, 4H), 1.29-1.37(m, 1H), 1.23-1.29 (m, 1H). MS (m/z): 489.5 [MH]⁺.

Example 223:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E223)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-5-methylpyrazine(p185, 37 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E223, 37.7 mg, y=63%). NMR: ¹H NMR (Acetone-d₆) δ: 9.24 (d, 1H),8.64 (s, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 3.97 (s, 3H), 3.22-3.40 (m,2H), 2.63 (s, 3H), 2.59-2.96 (m, 6H), 2.25-2.34 (m, 1H), 1.89-2.04 (m,4H), 1.21-1.39 (m, 2H). MS (m/z): 489.4 [MH]⁺.

Example 224:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E224)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-3-methylpyrazine(p186, 37 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E224, 37.8 mg, y=63%). NMR: ¹H NMR (Acetone-d₆) δ: 8.62 (s, 2H),7.60-7.68 (m, 2H), 7.39-7.46 (m, 2H), 3.77 (s, 3H), 3.33 (m, 2H), 2.82(s, 3H), 2.62-2.83 (m, 6H), 2.25-2.34 (m, 1H), 1.92-2.05 (m, 4H),1.32-1.38 (m, 1H), 1.22-1.31 (m, 1H). MS (m/z): 489.5 [MH]⁺.

Example 225 and 226:(1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E225) and(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E226)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E224, 37.8 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 30% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 500 μL Injection 12mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E225, 10.2 mg). Enantiomer 1: ret. time 3.8 min, 100% ee. MS(m/z): 489.5 [MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E226, 11.3 mg). Enantiomer 2: ret. time 5.1 min, 99.8% ee. MS(m/z): 489.5 [MH]⁺.

Example 227:(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 2, E227)

(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E226, 11.3 mg) was dissolved in Et₂O/DCM and treated with 1.2 eqof HCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E227, 11.7 mg). MS (m/z): 489.4[MH]⁺.

Example 228:5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide(CIS, E228)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 15 mg, 0.064 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine-2-carboxamide(p187, 20 mg, 0.064 mmol), Na₂CO₃ (8 mg, 0.077 mmol) and NaI (12 mg,0.077 mmol) in DMF (0.1 mL) affording5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide(CIS, E228, 14.4 mg, y=43%). NMR: ¹H NMR (Acetone-d₆) δ: 9.28-9.42 (m,2H), 7.93-8.07 (m, 1H), 7.59-7.68 (m, 2H), 7.38-7.45 (m, 2H), 7.02-7.15(m, 1H), 4.04 (s, 3H), 3.35 (d, 2H), 2.57-2.93 (m, 8H), 2.30 (br. s.,1H), 1.98 (br. s., 2H), 1.22-1.39 (m, 2H). MS (m/z): 518.4 [MH]⁺.

Example 229:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E229)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazole(p188, 34 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E229, 13 mg, y=20%). NMR: ¹H NMR (Acetone-d₆) δ: 7.62 (d, 3H),7.36-7.45 (m, 3H), 3.82 (s, 3H), 3.28-3.45 (m, 3H), 2.40-2.71 (m, 6H),2.23-2.34 (m, 2H), 1.97 (br. s., 2H), 1.31 (br. s., 2H), 1.22-1.26 (m,1H). MS (m/z): 464.4 [MH]⁺.

Example 230:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E230)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazole(p189, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E230, 54 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ: 7.64 (d, 2H),7.35 (d, 2H), 6.90 (s, 1H), 3.89 (s, 3H), 3.36 (m, 3H), 2.75 (d, 1H),2.55-2.66 (m, 5H), 2.39 (s, 3H), 2.24-2.30 (m, 1H), 1.93-2.02 (m, 2H),1.61-1.72 (m, 1H), 1.37-1.48 (m, 1H), 1.24-1.29 (m, 1H), 1.21 (s, 1H).MS (m/z): 478.4 [MH]⁺.

Example 231:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E231)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazole(p189, 36 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E231, 38 mg, y=64%). NMR: ¹H NMR (Acetone-d₆) δ: 7.58-7.65 (m,2H), 7.37-7.41 (m, 2H), 6.88-6.91 (m, 1H), 3.84 (s, 3H), 3.28 (m, 2H),2.81-2.90 (m, 2H), 2.60 (br. s., 3H), 2.38 (s, 3H), 2.23-2.30 (m, 1H),1.84-2.03 (m, 5H), 1.29-1.34 (m, 1H), 1.23 (m, 1H). MS (m/z): 478.1[MH]⁺.

Example 232 and 233:(1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E232) and(1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E233)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E231, 38 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 50/50% v/v Flow rate (ml/min) 17 ml/min DADdetection 220 nm Loop 1000 μL Injection 17 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E232, 13 mg). Enantiomer 1: ret. time 10.1 min, 100% ee, MS (m/z):478.5 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E233, 10.8 mg), Enantiomer 2: ret. time 14.7 min, 100% ee, MS(m/z): 478.5 [MH]⁺.

Example 234:(1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E234)

(1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E232, 13 mg) was dissolved in Et₂O/DCM and treated with 1.2 eq ofHCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E234, 10.8 mg). MS (m/z): 478.5[MH]⁺.

Example 235:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E235)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazole(p190, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E235, 56 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ: 9.15 (s, 1H),7.64 (d, 2H), 7.39 (d, 2H), 3.62 (s, 3H), 3.36 (s, 2H), 2.72 (br. s.,5H), 2.50 (s, 3H), 2.28-2.36 (m, 1H), 1.97-2.06 (m, 3H), 1.67-1.79 (m,1H), 1.41-1.53 (m, 1H), 1.23-1.35 (m, 3H). MS (m/z): 494.4 [MH]⁺.

Example 236:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E236)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazole(p190, 38 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E236, 25 mg, y=40%). NMR: ¹H NMR (Acetone) δ: 9.15 (s, 1H),7.60-7.67 (m, 2H), 7.37-7.42 (m, 2H), 3.58 (s, 3H), 3.25 (m, 2H),2.72-2.77 (m, 2H), 2.60-2.67 (m, 1H), 2.46-2.56 (m, 6H), 2.21-2.26 (m,1H), 1.95-2.03 (m, 2H), 1.82-1.92 (m, 2H), 1.30 (m, 1H), 1.22 (m, 1H).MS (m/z): 494.5 [MH]⁺.

Example 237 and 238:(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E237) and(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E238)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E236, 25 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 65/35% v/v Flow rate (ml/min) 18 ml/min DADdetection 220 nm Loop 500 μL Injection 12 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E237, 7 mg). Enantiomer 1: ret. time 6.2 min, 100% ee. MS (m/z):494.0 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E238, 7 mg). Enantiomer 2: ret. time 8.0 min, 100% ee. MS (m/z):494.0 [MH]⁺.

Example 239:(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E239)

(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E237, 7 mg) was dissolved in Et₂O/DCM and treated with 1.2 eq ofHCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E239, 7.6 mg). MS (m/z): 494.0[MH]⁺.

Example 240:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E240)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole(p191, 63 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E240, 61 mg, y=61%). NMR: ¹H NMR (Acetone-d₆) δ: 8.04 (d, 1H),7.81 (d, 1H), 7.63 (d, 2H), 7.36-7.44 (m, 2H), 4.06 (s, 3H), 3.39 (m,2H), 2.96 (br. s., 5H), 2.26-2.39 (m, 1H), 2.01-2.05 (m, 3H), 1.66-1.79(m, 1H), 1.42-1.53 (m, 1H), 1.21-1.37 (m, 3H). MS (m/z): 480.4 [MH]⁺.

Example 241:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E241)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole(p191, 40 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E241, 28 mg, y=48%). NMR: ¹H NMR (Acetone-d₆) δ: 8.03 (d, 1H),7.79 (d, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 4.02 (s, 3H), 3.19-3.37 (m,2H), 2.70-2.76 (m, 2H), 2.61 (d, 1H), 2.44-2.57 (m, 3H), 2.19-2.26 (m,1H), 1.92-2.02 (m, 2H), 1.82-1.91 (m, 2H), 1.28 (m, 1H), 1.20 (m, 1H).MS (m/z): 480.0 [MH]⁺.

Example 242 and 243:(1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E242) and(1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E243)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E241, 28 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phase n-Hexane/(Ethanol +0.1% isopropylamine) 65/35% v/v Flow rate (ml/min) 18 ml/min DADdetection 220 nm Loop 1000 μL Injection 13 mg/injection

affording(1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E242, 9 mg). Enantiomer 1: ret. time 10.6 min, 100% ee. MS (m/z):480.0 [MH]⁺ and(1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E243, 8 mg). Enantiomer 2: ret. time 17.7 min, 100% ee, MS (m/z):480.0 [MH]⁺.

Example 244:(1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E244)

(1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E242, 9 mg) was dissolved in Et₂O/DCM and treated with 1.2 eq ofHCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E244, 10 mg). MS (m/z): 480.0[MH]⁺.

Example 245:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E245)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 50 mg, 0.207 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole(p192, 62 mg, 0.228 mmol), Na₂CO₃ (26 mg, 0.248 mmol) and NaI (37 mg,0.248 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E245, 46.7 mg, y=47%). NMR: ¹H NMR (Acetone-d₆) δ: 8.15 (s, 1H),7.87 (s, 1H), 7.63 (d, 2H), 7.39 (br. s., 2H), 3.99 (s, 3H), 3.74 (s,3H), 3.26 (br. s., 2H), 2.48-2.76 (m, 5H), 2.28-2.38 (m, 1H), 1.94-2.03(m, 2H), 1.65-1.82 (m, 1H), 1.39-1.52 (m, 1H), 1.31 (br. s., 3H). MS(m/z): 477.4 [MH]⁺.

Example 246: (1R,3S/1S,3R)5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E246)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole(p192, 36 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E246, 31 mg, y=54%). NMR: ¹H NMR (Acetone-d₆) δ: 8.13-8.17 (m,1H), 7.86-7.89 (m, 1H), 7.60-7.65 (m, 2H), 7.36-7.41 (m, 2H), 4.00 (s,3H), 3.71 (s, 3H), 3.08-3.24 (m, 2H), 2.71-2.76 (m, 1H), 2.57-2.65 (m,1H), 2.43-2.54 (m, 3H), 2.20-2.26 (m, 2H), 1.95-2.04 (m, 3H), 1.78-1.87(m, 2H), 1.26-1.32 (m, 1H), 1.19-124 (m, 1H). MS (m/z): 477.5 [MH]⁺.

Example 247 and 248:(1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E247) and(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E248)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E246, 31 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 24% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 750 μL Injection 15mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E247, 9.7 mg). Enantiomer 1: ret. time 5.6 min, 96.2% ee. MS(m/z): 477.0 [MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E248, 10 mg). Enantiomer 2: ret. time 7.3 min, 100% ee. MS (m/z):477.0 [MH]⁺.

Example 249:(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 2, E249)

(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E248, 10 mg) was dissolved in Et₂O/DCM and treated with 1.2 eq ofHCl 2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E249, 8.8 mg). MS (m/z): 477.0[MH]⁺.

Example 250:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E250)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 35 mg, 0.15 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazole(p193, 30 mg, 0.15 mmol), Na₂CO₃ (19 mg, 0.18 mmol) and NaI (22 mg, 0.15mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E250, 31 mg, y=43%). NMR: ¹H NMR (Acetone-d₆) δ: 7.61 (d, 1H),7.54 (d, 2H), 7.22 (d, 2H), 6.51 (d, 1H), 4.15 (s, 3H), 3.56-3.60 (m,3H), 3.25-3.39 (m, 2H), 2.89 (d, 1H), 2.73 (br. s., 1H), 2.62 (br. s.,2H), 2.50 (d, 1H), 2.13-2.25 (m, 2H), 1.91-2.12 (m, 4H), 1.18-1.27 (m,2H). MS (m/z): 477.4 [MH]⁺.

Example 251 and 252:(1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E251) and(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 2, E252)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E250, 31 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Modifier (Methanol + 0.1%isopropylamine) 20% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 700 μL Injection 10.2mg/injection

affording(1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E251, 8.6 mg). Enantiomer 1: ret. time 6.6 min. MS (m/z): 477.4[MH]⁺ and(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E252, 8.6 mg), Enantiomer 2: ret. time 9.0 min. MS (m/z): 477.4[MH]⁺.

Example 253:(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 2, E253)

(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E252, 8.6 mg) was dissolved in DCM and treated with 1.1 eq of HCl2N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E253, 9 mg). MS (m/z): 477.4[MH]⁺.

Example 254:(1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E254)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-5-(furan-2-yl)-4-methyl-4H-1,2,4-triazole(p194, 34 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E254, 19.4 mg, y=32%). NMR: ¹H NMR (Acetone-d₆) δ: 7.80-7.83 (m,1H), 7.61 (d, 2H), 7.37 (d, 2H), 7.03 (m, 1H), 6.67-6.70 (m, 1H), 3.79(s, 3H), 3.11-3.28 (m, 2H), 2.70-2.76 (m, 1H), 2.57-2.67 (m, 1H),2.44-2.56 (m, 3H), 2.20-2.25 (m, 1H), 1.89-2.02 (m, 2H), 1.79-1.87 (m,2H), 1.46-1.55 (m, 1H), 1.25-1.31 (m, 1H), 1.17-1.24 (m, 1H). MS (m/z):463.0 [MH]⁺.

Example 255:(1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E255)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-5-(furan-3-yl)-4-methyl-4H-1,2,4-triazole(p195, 34 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E255, 27 mg, y=45%). NMR: ¹H NMR (Acetone-d₆) δ: 8.15-8.18 (m,1H), 7.74-7.78 (m, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 6.94-6.97 (m, 1H),3.72 (s, 3H), 3.06-3.27 (m, 2H), 2.70-2.76 (m, 2H), 2.56-2.65 (m, 1H),2.42-2.55 (m, 3H), 2.19-2.24 (m, 1H), 1.92-2.00 (m, 2H), 1.81 (m, 2H),1.24-1.30 (m, 1H), 1.17-1.24 (m, 1H). MS (m/z): 463.0 [MH]⁺.

Example 256:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E256)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazole(p196, 36 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E256, 29.7 mg, y=50%). NMR: ¹H NMR (Acetone-d₆) δ: 7.66-7.71 (m,1H), 7.60 (d, 3H), 7.33-7.41 (m, 2H), 7.22-7.27 (m, 1H), 3.79 (s, 3H),3.10-3.29 (m, 2H), 2.69-2.76 (m, 2H), 2.57-2.65 (m, 1H), 2.43-2.57 (m,3H), 2.19-2.25 (m, 1H), 1.92-2.03 (m, 2H), 1.77-1.87 (m, 2H), 1.25-1.30(m, 1H), 1.17-1.23 (m, 1H). MS (m/z): 479.0 [MH]⁺.

Example 257:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E257)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazole(p197, 36 mg, 0.132 mmol), Na₂CO₃ (15 mg, 0.144 mmol) and NaI (22 mg,0.144 mmol) in DMF (0.135 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E257, 27.3 mg, y=45%). NMR: ¹H NMR (Acetone-d₆) δ: 7.95-7.98 (m,1H), 7.66-7.71 (m, 1H), 7.57-7.64 (m, 3H), 7.37 (d, 2H), 3.76 (s, 3H),3.10-3.28 (m, 2H), 2.69-2.76 (m, 2H), 2.56-2.65 (m, 1H), 2.42-2.55 (m,3H), 2.19-2.26 (m, 1H), 1.92-2.02 (m, 2H), 1.77-1.87 (m, 2H), 1.28 (m,1H), 1.20 (m, 1H). MS (m/z): 479.0 [MH]⁺.

Example 258:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E258)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 38 mg, 0.16 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazole(p198, 48 mg, 0.176 mmol), Na₂CO₃ (20 mg, 0.192 mmol) and NaI (29 mg,0.192 mmol) in DMF (0.17 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E258, 33.2 mg, y=42%). NMR: ¹H NMR (Acetone-d₆) δ: 7.55-7.65 (m,2H), 7.34-7.40 (m, 2H), 6.91-6.97 (m, 1H), 6.47-6.53 (m, 1H), 6.17-6.23(m, 1H), 3.84 (s, 3H), 3.62 (s, 3H), 3.11-3.29 (m, 2H), 2.68-2.76 (m,2H), 2.61 (d, 1H), 2.43-2.57 (m, 3H), 2.20-2.25 (m, 1H), 1.78-2.01 (m,4H), 1.26-1.31 (m, 1H), 1.17-1.23 (m, 1H). MS (m/z): 476.02 [MH]⁺.

Preparation 259:(1S,3S/1R,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p259)

To a solution of(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 100 mg, 0.41 mmol) in THF (0.8 mL), in a vial, DIPEA (0.21mL, 1.23 mmol) and 1-bromo-3-chloropropane (0.37 mL, 3.73 mmol) wereadded, the vial was sealed and the resulting mixture was shaken at 65°C. for 3 hrs. After cooling at RT the reaction mixture was diluted withEA and filtered. The filtrate was concentrated under reduced pressureand the crude material was purified by FC on silica gel (eluting withDCM/MeOH from 100/0 to 96/4) affording(1S,3S/1R,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p259, TRANS, 75 mg, y=58%) as pale yellow oil. MS (m/z): 318.2 [MH]⁺.

Example 259:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E259)

A sealed vial containing a mixture of(1S,3S/1R,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p259, 40 mg, 0.13 mmol),4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazole-3-thiol (p109, 31mg, 0.16 mmol), Na₂CO₃ (17 mg, 0.16 mmol) and NaI (15 mg, 0.13 mmol) andDMF (0.2 mL) was shaken O/N at 60° C. in a PLS apparatus. The mixturewas diluted with EA, the organic phase was washed with water, dried oversodium sulfate and the solvent removed under reduced pressure. The crudematerial was purified by FC on silica gel (eluting with DCM/MeOH from100/0 to 96/6) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, 15 mg).

The latter was dissolved in DCM (0.1 mL) then 2N HCl/ether (1.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.O/N, affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E259, 15 mg, y=22%). NMR: ¹H NMR (DMSO-d₆) δ:10.58(br. s., 1H), 9.79 (s, 1H), 7.67 (m, 2H), 7.46 (m, 2H), 3.90 (s, 3H),3.50-3.70 (m, 4H), 3.16-3.40 (m, 6H), 3.00-3.12 (m, 1H), 2.37-2.48 (m,1H), 1.80-1.97 (m, 1H), 1.29-1.56 (m, 3H). MS (m/z): 481.4 [MH]⁺.

Example 260:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E260)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 30 mg, 0.12 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2,3-thiadiazole(p199, 34 mg, 0.12 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, E260, 6 mg, y=9%). NMR: ¹H NMR (CDCl₃) δ: 9.34 (s, 1H), 7.54 (d,2H), 7.22 (d, 2H), 4.04 (s, 3H), 3.33 (d, 2H), 2.80-2.90 (m, 1H),2.63-2.74 (m, 1H), 2.58 (br. s., 2H), 2.42-2.49 (m, 1H), 2.16 (d, 2H),2.01 (br. s., 5H), 1.21 (s, 2H). MS (m/z): 481.4 [MH]⁺.

Preparation 260:(1R,3S)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p260)

To a solution of(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 48 mg, 0.2 mmol) in THF (0.4 mL), in a vial, DIPEA(0.10 mL, 0.6 mmol) and 1-bromo-3-chloropropane (0.18 mL, 1.79 mmol)were added, the vial was sealed and the resulting mixture was shaken at65° C. for 3 hrs. After cooling at RT the reaction mixture was dilutedwith EA and filtered. The filtrate was concentrated under reducedpressure and the crude material was purified by FC on silica gel(eluting with DCM/MeOH from 100/0 to 97/3) affording(1R,3S)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p260, 40 mg, y=62%) as pale yellow oil. MS (m/z):318.2 [MH]⁺.

Example 261:(1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E261)

A sealed vial containing a mixture of(1R,3S)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p260, 30 mg, 0.13 mmol),4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazole-3-thiol (p109, 28mg, 0.14 mmol), Na₂CO₃ (17 mg, 0.16 mmol) and NaI (15 mg, 0.13 mmol) andDMF (0.2 mL) was shaken O/N at 60° C. in a PLS apparatus. The mixturewas diluted with EA, the organic phase was washed with water, dried oversodium sulfate and the solvent removed under reduced pressure. The crudematerial was purified by FC on silica gel (eluting with DCM/MeOH from100/0 to 94/6) then purified again by FC on NH column (eluting withCy/EA from 100/0 to 30/70) to give(1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(18 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (1.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.O/N, affording(1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E261, 19 mg, y=28%). as pale yellowsolid. NMR: ¹H NMR (DMSO-d₆) δ: 10.37-10.66 (m, 1H), 9.78 (d, 1H),7.61-7.71 (m, 2H), 7.39-7.48 (m, 2H), 3.87 (d, 3H), 3.65-3.76 (m, 1H),3.39-3.47 (m, 1H), 2.94-3.32 (m, 6H), 2.62-2.71 (m, 1H), 2.19-2.44 (m,2H), 1.94-2.15 (m, 3H), 1.27-1.52 (m, 2H). MS (m/z): 481.3 [MH]⁺.

Example 262:(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E262)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl)}-4-methyl-1,2,3-thiadiazole(p200, 34 mg, 0.12 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(29 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (1.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.O/N, affording(1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E262, 31 mg, y=49%). NMR: ¹H NMR(DMSO-d₆) δ: 10.39-10.67 (m, 1H), 7.66 (d, 2H), 7.44 (d, 2H), 3.69 (br.s., 1H), 3.51-3.59 (m, 3H), 3.37-3.47 (m, 1H), 2.93-3.29 (m, 5H), 2.80(s, 3H), 2.61-2.72 (m, 1H), 2.19-2.45 (m, 2H), 1.93-2.15 (m, 3H),1.27-1.52 (m, 2H). MS (m/z): 495.3 [MH]⁺.

Example 263:(1R,3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E263)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol),3-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,3-oxazol-2-yl)pyridine(p201, 34 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E263, 34.2 mg, y=66%). NMR: ¹H NMR (Acetone-d₆) δ:9.29-9.36 (m, 1H), 8.77-8.80 (m, 1H), 8.67-8.69 (m, 1H), 8.44-8.49 (m,1H), 7.60-7.67 (m, 3H), 7.37-7.45 (m, 2H), 3.97 (s, 3H), 3.20-3.35 (m,2H), 2.61-2.98 (m, 5H), 2.27-2.34 (m, 1H), 2.09-2.15 (m, 1H), 1.89-2.03(m, 4H), 1.33-1.40 (m, 1H), 1.23-1.29 (m, 1H). MS (m/z): 541.4 [MH]⁺.

Example 264:(1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E264)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol),5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-phenoxypyridine(p202, 37 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.2 mL) affording(1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E264, 27 mg, y=49%). NMR: ¹H NMR (Acetone-d₆) δ:8.45-8.50 (m, 1H), 8.16-8.22 (m, 1H), 7.60-7.66 (m, 2H), 7.44-7.52 (m,2H), 7.34-7.42 (m, 2H), 7.20-7.32 (m, 3H), 7.14-7.20 (m, 1H), 3.70 (s,3H), 3.11-3.32 (m, 2H), 2.71-2.77 (m, 1H), 2.59-2.66 (m, 1H), 2.44-2.58(m, 3H), 2.20-2.27 (m, 2H), 1.79-2.02 (m, 4H), 1.26-1.33 (m, 1H), 1.21(m, 1H). MS (m/z): 566.4 [MH]⁺.

Example 265:(1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloride (CIS, Enantiomer 1, E265)

(1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E264, 27 mg) was dissolved in MeOH and treated with2.2 eq of HCl 1N in Et₂O affording(1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanedihydrochloric salt (CIS, Enantiomer 1, E265, 30.3 mg). MS (m/z): 566.4[MH]⁺.

Example 266:(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E266)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 20 mg, 0.083 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazole(p203, 28 mg, 0.091 mmol), Na₂CO₃ (11 mg, 0.1 mmol) and NaI (15 mg, 0.1mmol) in DMF (0.1 mL) affording(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E266, 18.7 mg, y=44%). NMR: ¹H NMR (Acetone-d₆) δ:9.27-9.30 (m, 1H), 8.77-8.80 (m, 1H), 7.70-7.73 (m, 1H), 7.62 (d, 2H),7.41 (d, 2H), 7.19 (t, 1H), 3.68-3.71 (m, 3H), 3.30 (m, 2H), 2.52-2.76(m, 5H), 2.13-2.32 (m, 2H), 1.88-2.04 (m, 4H), 1.30-1.36 (m, 1H), 1.24(m, 1H). MS (m/z): 514.3 [MH]⁺.

Example 267:(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E267)

(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E266, 18.7 mg) was dissolved in DCM and treated with1.1 eq of HCl 2N in Et₂O affording(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl)}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E267, 17 mg). MS (m/z): 514.3[MH]⁺.

Example 268:(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E268)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazole(p204, 35 mg, 0.113 mmol), Na₂CO₃ (13 mg, 0.123 mmol) and NaI (18 mg,0.123 mmol) in DMF (0.1 mL) affording(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(6.5 mg).

The latter was dissolved in DCM and treated with 1.1 eq of HCl 2M inEt₂O, then concentrated under reduced pressure, triturated with Et₂O anddried under high vacuum affording(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E268, 5.5 mg, y=10%). NMR: ¹H NMR(DMSO-d₆) δ: 10.39-10.67 (m, 1H), 9.40 (s, 1H), 9.07 (s, 1H), 7.98 (d,1H), 7.75 (d, 1H), 7.67 (d, 2H), 7.46 (d, 2H), 3.65-3.77 (m, 4H),2.94-3.48 (m, 7H), 1.95-2.46 (m, 5H), 1.28-1.54 (m, 2H). MS (m/z): 514.3[MH]⁺.

Example 269:(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E269)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazole(p205, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording(1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E269, 25.4 mg, y=49%). NMR: ¹H NMR (Acetone-d₆) δ:9.16-9.25 (m, 1H), 8.67-8.72 (m, 1H), 8.07-8.12 (m, 1H), 7.60-7.66 (m,2H), 7.42-7.48 (m, 1H), 7.36-7.42 (m, 2H), 3.90 (s, 3H), 3.21-3.37 (m,2H), 2.72-2.76 (m, 1H), 2.61-2.68 (m, 1H), 2.46-2.58 (m, 3H), 2.21-2.28(m, 1H), 2.10-2.13 (m, 1H), 1.94-2.05 (m, 2H), 1.83-1.94 (m, 2H),1.27-1.32 (m, 1H), 1.22 (m, 1H). MS (m/z): 514.3 [MH]⁺.

Example 270:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E270)

The compound was prepared as in Example 1, reacting(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, p24, 26 mg, 0.1 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazole(p205, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl)}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E270, 24 mg, y=45%). NMR: ¹H NMR (DMSO-d₆) δ: 9.38(s, 1H), 8.68-8.74 (m, 1H), 8.15-8.20 (m, 1H), 7.60-7.66 (m, 1H),7.47-7.53 (m, 1H), 7.34-7.39 (m, 1H), 7.27-7.34 (m, 1H), 3.73 (s, 3H),3.17 (m, 2H), 2.75 (d, 1H), 2.36-2.48 (m, 4H), 2.23 (s, 1H), 1.91-1.98(m, 2H), 1.87 (d, 1H), 1.71-1.82 (m, 2H), 1.37 (m, 1H), 1.21 (m, 1H). MS(m/z): 532.3 [MH]⁺.

Example 271:(1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E271)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazole(p206, 32 mg, 0.1 mmol), Na₂CO₃ (13 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.2 mL) affording(1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl})-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E271, 29.7 mg, y=58%). NMR: ¹H NMR (Acetone-d₆) δ:8.53-8.63 (m, 1H), 7.76-7.85 (m, 1H), 7.63 (s, 3H), 7.36-7.44 (m, 2H),3.77 (s, 3H), 3.16-3.35 (m, 2H), 2.81 (s, 3H), 2.72-2.77 (m, 1H),2.59-2.68 (m, 1H), 2.46-2.56 (m, 3H), 2.21-2.28 (m, 2H), 1.83-2.03 (m,4H), 1.27-1.32 (m, 1H), 1.19-1.25 (m, 1H). MS (m/z): 528.4 [MH]⁺.

Example 272:(1R,3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl)}-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E272)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 34 mg, 0.14 mmol),3-[(3-chloropropyl)sulfanyl]-5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazole(p207, 22 mg, 0.071 mmol), Na₂CO₃ (9 mg, 0.009 mmol) and NaI (10 mg,0.007 mmol) in DMF (0.2 mL) affording(1R,3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E272, 16 mg, y=44%). NMR: ¹H NMR (DMSO-d₆) δ:13.01-13.19 (m, 1H), 8.57 (s, 1H), 8.15-8.21 (m, 1H), 8.05 (s, 1H),7.57-7.63 (m, 2H), 7.29-7.34 (m, 2H), 3.94-4.01 (m, 3H), 3.08-3.22 (m,2H), 2.66-2.76 (m, 1H), 2.36-2.50 (m, 4H), 2.21 (m, 1H), 1.82-1.98 (m,3H), 1.72-1.81 (m, 2H), 1.23-1.29 (m, 1H), 1.15-1.20 (m, 1H). MS (m/z):514.4 [MH]⁺.

Example 273:(1R,3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E273)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 27 mg, 0.11 mmol),5-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)-1H-1,2,3,4-tetrazole(p208, 34 mg, 0.10 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (15 mg, 0.1mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E273, 9.7 mg, y=16%). NMR: ¹H NMR (DMSO-d₆) δ: 8.14(d, 2H), 7.73 (d, 2H), 7.60-7.66 (m, 2H), 7.33-7.38 (m, 2H), 3.63 (s,3H), 3.09-3.19 (m, 2H), 2.88-3.01 (m, 1H), 2.56-2.85 (m, 4H), 2.28 (m,1H), 2.19 (br. s., 1H), 2.00-2.07 (m, 1H), 1.89-1.98 (m, 1H), 1.78-1.87(m, 2H), 1.30-1.36 (m, 1H), 1.19-1.25 (m, 1H). MS (m/z): 541.4 [MH]⁺.

Example 274:(1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E274)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol),2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)-1,3,4-oxadiazole(p209, 47 mg, 0.14 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(15 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (1.1 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.O/N affording(1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E274, 15 mg, y=22%). NMR: ¹H NMR(DMSO-d₆) δ: 10.41-10.75 (m, 1H), 9.44 (s, 1H), 8.16-8.26 (m, 2H),7.93-8.02 (m, 2H), 7.61-7.71 (m, 2H), 7.38-7.50 (m, 2H), 3.63-3.77 (m,4H), 2.92-3.51 (m, 7H), 1.94-2.70 (m, 5H), 1.26-1.53 (m, 2H). MS (m/z):541.4 [MH]⁺.

Example 275:(1R,3S)-5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E275)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)-5-methyl-1,2,4-oxadiazole(p210, 39 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E275, 33 mg, y=60%). NMR: ¹H NMR (Acetone-d₆) δ:8.24 (d, 2H), 7.97 (d, 2H), 7.63 (d, 2H), 7.40 (d, 2H), 3.77 (s, 3H),3.17-3.34 (m, 2H), 2.72 (s, 3H), 2.60-2.70 (m, 1H), 2.48-2.60 (m, 3H),2.23 (s, 1H), 2.11 (br. s., 1H), 1.95-2.03 (m, 2H), 1.84-1.95 (m, 3H),1.30 (m, 1H), 1.23 (m, 1H). MS (m/z): 555.4 [MH]⁺.

Example 276:(1R,3S)-5-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E276)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazole(p211, 37 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording(1R,3S)-5-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E276, 36 mg, y=67%). NMR: ¹H NMR (Acetone-d₆) δ:8.96 (s, 2H), 7.95-8.01 (m, 2H), 7.87-7.94 (m, 2H), 7.58-7.64 (m, 2H),7.35-7.41 (m, 2H), 3.74 (s, 3H), 3.16-3.34 (m, 2H), 2.70-2.76 (m, 1H),2.59-2.66 (m, 1H), 2.42-2.57 (m, 3H), 2.19-2.26 (m, 1H), 2.07-2.11 (m,1H), 1.80-2.03 (m, 4H), 1.26-1.31 (m, 1H), 1.21 (m, 1H). MS (m/z): 540.4[MH]⁺.

Example 277:(1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E277)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.096 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole(p212, 35 mg, 0.1 mmol), Na₂CO₃ (12 mg, 0.115 mmol) and NaI (17 mg,0.115 mmol) in DMF (0.15 mL) affording(1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E277, 31 mg, y=60%). NMR: ¹H NMR (Acetone-d₆) δ:8.19-8.25 (m, 2H), 8.11 (d, 1H), 7.92-7.97 (m, 2H), 7.62 (d, 2H),7.37-7.44 (m, 3H), 3.76 (s, 3H), 3.20-3.34 (m, 2H), 2.47-2.72 (m, 6H),2.28 (br. s., 1H), 1.86-2.02 (m, 4H), 1.33 (br. s., 1H), 1.24 (br. s.,1H). MS (m/z): 540.4 [MH]⁺.

Example 278:(1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E278)

(1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E277, 31 mg) was dissolved in MeOH and treated with1.1 eq of HCl 2N in Et₂O affording(1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 1, E278, 30 mg). MS (m/z): 540.4[MH]⁺.

Example 279:(1R,3S)-5-[3-({4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E279)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole(p239, 37 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording(1R,3S)-5-[3-({4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, Enantiomer 1, E279, 31 mg, y=57%). NMR: ¹H NMR (Acetone-d₆) δ:8.42-8.44 (m, 1H), 8.19-8.25 (m, 1H), 8.11 (d, 1H), 7.89-7.94 (m, 1H),7.70-7.79 (m, 1H), 7.63 (d, 2H), 7.43 (d, 2H), 7.38 (d, 1H), 3.77 (s,3H), 3.19-3.38 (m, 2H), 2.64-3.04 (m, 6H), 2.28-2.37 (m, 2H), 1.93-2.05(m, 3H), 1.35-1.41 (m, 1H), 1.25-1.30 (m, 1H). MS (m/z): 540.4 [MH]⁺.

Example 280:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E280)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide(p213, 35 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E280, 38.5 mg, y=72%). NMR: ¹H NMR (Acetone-d₆) δ:8.12 (d, 2H), 7.87 (d, 2H), 7.55-7.65 (m, 2H), 7.39 (d, 2H), 6.68-6.79(m, 1H), 3.73 (s, 3H), 3.17-3.32 (m, 2H), 2.71-2.76 (m, 1H), 2.59-2.68(m, 1H), 2.44-2.58 (m, 3H), 2.20-2.29 (m, 1H), 2.08-2.12 (m, 1H),1.82-2.04 (m, 4H), 1.30 (m, 1H), 1.22 (m, 1H). MS (m/z): 516.4 [MH]⁺.

Example 281:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloride (CIS, Enantiomer 1, E281)

4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E280, 38.5 mg) was dissolved in DCM/Et₂O and treatedwith 1.1 eq of HCl 2N in Et₂O affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloric salt (CIS, Enantiomer 1, E281, 40.7 mg). MS (m/z): 516.4[MH]⁺.

Example 282:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile(CIS, Enantiomer 1, E282)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.103 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzonitrile(p214, 50 mg, 0.113 mmol, considered 60% purity), Na₂CO₃ (13 mg, 0.123mmol) and NaI (18 mg, 0.123 mmol) in DMF (0.1 mL) affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile(CIS, Enantiomer 1, E282, 40 mg, y=78%). NMR: ¹H NMR (Acetone-d₆) δ:7.93-8.05 (m, 4H), 7.54-7.68 (m, 2H), 7.33-7.44 (m, 2H), 3.76 (s, 3H),3.19-3.34 (m, 2H), 2.72-2.77 (m, 1H), 2.60-2.68 (m, 1H), 2.45-2.57 (m,3H), 2.20-2.28 (m, 1H), 2.08-2.13 (m, 1H), 1.81-2.04 (m, 4H), 1.26-1.32(m, 1H), 1.22 (m, 1H). MS (m/z): 498.4 [MH]⁺.

Example 283:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrilehydrochloride (CIS, Enantiomer 1, E283)

4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl})sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E282,40 mg) was dissolved in MeOH/Et₂O and treated with 1.1 eq of HCl 2N inEt₂O affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrilehydrochloric salt (CIS, Enantiomer 1, E283, 36.1 mg). MS (m/z): 498.4[MH]⁺.

Example 284:1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}ethan-1-onehydrochloride (CIS, Enantiomer 1, E284)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)ethan-1-one(p215, 34 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.113 mL) affording1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl})sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}) ethan-1-one (34.4 mg).

The latter was dissolved in DCM/Et₂O and treated with 2N HCl/ether (1.2eq) affording1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}ethan-1-onehydrochloride (CIS, Enantiomer 1, E284, 34.5 mg, y=62%). NMR: ¹H NMR(DMSO-d₆) δ: 10.14-10.44 (m, 1H), 8.12 (d, 2H), 7.88 (d, 2H), 7.65 (d,2H), 7.38-7.48 (m, 2H), 3.68-3.74 (m, 1H), 3.64 (d, 3H), 3.38-3.47 (m,1H), 3.21 (d, 6H), 2.65 (s, 3H), 2.20-2.45 (m, 2H), 1.92-2.14 (m, 3H),1.26-1.53 (m, 2H). MS (m/z): 515.4 [MH]⁺.

Example 285:4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzene-1-sulfonamide(CIS, Enantiomer 1, E285)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzene-1-sulfonamide(p216, 38 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]benzene-1-sulfonamide(CIS, Enantiomer 1, E285, 32.9 mg, y=60%). NMR: ¹H NMR (Acetone) δ: 8.05(s, 2H), 7.97 (s, 2H), 7.58-7.66 (m, 2H), 7.32-7.42 (m, 2H), 6.70-6.76(m, 1H), 3.74 (s, 3H), 3.26 (m, 2H), 2.79 (br. s., 2H), 2.45-2.70 (m,4H), 2.21-2.26 (m, 1H), 1.81-2.02 (m, 4H), 1.29 (m, 1H), 1.21 (m, 1H).MS (m/z): 552.3 [MH]⁺.

Example 286:2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetonitrile(CIS, Enantiomer 1, E286)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)acetonitrile(p217, 31 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl)}acetonitrile(CIS, Enantiomer 1, E286, 27 mg, y=55%). NMR: ¹H NMR (Acetone-d₆) δ:7.79-7.85 (m, 2H), 7.60-7.66 (m, 4H), 7.36-7.43 (m, 2H), 4.11 (s, 2H),3.71 (s, 3H), 3.15-3.34 (m, 2H), 2.72-2.76 (m, 2H), 2.59-2.68 (m, 1H),2.47-2.58 (m, 3H), 2.22-2.28 (m, 1H), 1.81-2.04 (m, 4H), 1.27-1.34 (m,1H), 1.22 (m, 1H). MS (m/z): 512.3 [MH]⁺.

Example 287:2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl)}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl)}acetamide(CIS, Enantiomer 1, E287)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.1 mmol),2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)acetamide(p218, 35 mg, 0.11 mmol), Na₂CO₃ (13 mg, 0.12 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.1 mL) affording2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetamide(CIS, Enantiomer 1, E287, 31 mg, y=61%). NMR: ¹H NMR (DMSO-d₆) δ:7.58-7.68 (m, 4H), 7.50-7.56 (m, 1H), 7.41-7.47 (m, 2H), 7.29-7.36 (m,2H), 6.90-6.98 (m, 1H), 3.58 (s, 3H), 3.48 (s, 2H), 3.12 (d, 2H),2.64-2.74 (m, 1H), 2.37-2.48 (m, 4H), 2.17-2.25 (m, 1H), 1.96 (d, 3H),1.76 (s, 2H), 1.28 (m, 1H), 1.18 (m, 1H). MS (m/z): 530.4 [MH]⁺.

Example 288:3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E288)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 25 mg, 0.103 mmol),3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide(p219, 35 mg, 0.113 mmol), Na₂CO₃ (13 mg, 0.123 mmol) and NaI (18 mg,0.123 mmol) in DMF (0.1 mL) affording3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E288, 35 mg, y=66%). NMR: ¹H NMR (Acetone-d₆) δ:8.27 (s, 1H), 8.08-8.15 (m, 1H), 7.88-7.95 (m, 1H), 7.59-7.72 (m, 4H),7.39 (d, 2H), 6.68-6.83 (m, 1H), 3.72 (s, 3H), 3.16-3.32 (m, 2H),2.70-2.77 (m, 1H), 2.59-2.68 (m, 1H), 2.42-2.58 (m, 3H), 2.21-2.29 (m,1H), 1.93-2.07 (m, 3H), 1.81-1.91 (m, 2H), 1.26-1.34 (m, 1H), 1.19-1.25(m, 1H). MS (m/z): 516.4 [MH]⁺.

Example 289:3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloride (CIS, Enantiomer 1, E289)

3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(CIS, Enantiomer 1, E288, 35 mg) was dissolved in Et₂O and treated with1.1 eq of HCl 2N in Et₂O affording3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloric salt (CIS, Enantiomer 1, E289, 31.5 mg). MS (m/z): 516.4[MH]⁺.

Example 290:2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloride (CIS, Enantiomer 1, E290)

The compound was prepared as in Example 1, reacting(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 30 mg, 0.12 mmol),2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide(p220, 43 mg, 0.14 mmol), Na₂CO₃ (15 mg, 0.14 mmol) and NaI (18 mg, 0.12mmol) in DMF (0.2 mL) affording2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide(9 mg).

The latter was dissolved in DCM (0.2 mL) then 2N HCl/ether (1.2 eq) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.O/N affording2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamidehydrochloride (CIS, Enantiomer 1, E290, 9.7 mg, y=22%). NMR: ¹H NMR(DMSO-d₆) δ: 10.40-11.03 (m, 2H), 7.30-8.02 (m, 7H), 6.87 (br. s., 1H),3.60-3.82 (m, 3H), 3.05-3.47 (m, 5H), 2.61-3.05 (m, 4H), 1.82-2.48 (m,4H), 1.22-1.56 (m, 2H). MS (m/z): 516.4 [MH]⁺.

Example 291:1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl}propan-2-ol(CIS, E291) diastereisomeric mixture

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 70 mg, 0.29 mmol),1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propan-2-ol(p240, 117 mg, 0.41 mmol), Na₂CO₃ (47 mg, 0.444 mmol) and NaI (67 mg,0.444 mmol) in DMF (0.28 mL) affording1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl}propan-2-ol(CIS, E291, 13 mg, y=9%) as diastereomeric mixture. NMR: ¹H NMR(Acetone-d₆) δ: 8.28 (s, 1H), 7.61 (d, 2H), 7.31-7.43 (m, 2H), 3.77 (d,3H), 3.52-3.59 (m, 1H), 3.41-3.49 (m, 1H), 3.11-3.24 (m, 2H), 2.57 (br.s., 2H), 2.43 (s, 3H), 2.20-2.28 (m, 2H), 1.92-2.00 (m, 2H), 1.88-1.92(m, 1H), 1.26-1.35 (m, 2H), 1.17-1.24 (m, 1H). MS (m/z): 494.4 [MH]⁺.

Example 292:(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl)}-5-azaspiro[2.4]heptane(CIS, E292)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(CIS, p23, 50 mg, 0.19 mmol) and4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal (p247, 100 mg,0.25 mmol), were dissolved in DCM (5 mL) and stirred for 15 min beforeadding NaBH(OAc)₃ (80 mg, 0.38 mmol). The reaction mixture was stirredat RT O/N. Then it was diluted with water and DCM and extracted severaltimes with DCM. Organic phase was evaporated and the residue waspurified by FC on silica gel (eluent from DCM to MeOH) to obtain thetitle compound(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E292, 45 mg, y=49%). NMR: ¹H NMR (Acetone-d₆) δ: 7.43-7.54 (m,2H), 7.32 (m, 1H), 3.97 (m, 2H), 3.57 (s, 3H), 3.51 (d, 2H), 3.00-3.10(m, 1H), 2.70-2.78 (m, 1H), 2.65 (d, 2H), 2.53-2.60 (m, 1H), 2.32-2.43(m, 3H), 2.22-2.29 (m, 1H), 1.95-2.02 (m, 3H), 1.78-1.92 (m, 4H),1.67-1.77 (m, 2H), 1.44-1.53 (m, 2H), 1.32-1.38 (m, 1H), 1.20-1.26 (m,1H). MS (m/z): 481.1 [MH]⁺.

Example 293 and Example 294:(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E293, Enantiomer 1) and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E294, Enantiomer 2)

(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E292, 40 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2 cm), 5 um Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 80/20% v/v Flowrate (ml/min) 17 ml/min DAD detection 220 nm Loop 1000 μL Injection 21mg/injection

affording(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E293, 11 mg). Enantiomer 1: ret. time 6.4 min, 100% ee. MS (m/z):481.5 [MH]⁺ and(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E294, 11 mg). Enantiomer 2: ret. time 8.5 min, 100% ee. MS (m/z):481.5 [MH]⁺.

Example 295:(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptanehydrochloride (CIS, E295, Enantiomer 2)

(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane(CIS, E294, 11.5 mg) was treated with 1.1 eq of HCl in Et₂O affording(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptanehydrochloric salt (CIS, Enantiomer 2, E295, 11.8 mg). MS (m/z): 481.1[MH]⁺.

Example 296:(1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E296)

To a solution of 4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal(p247, 135 mg, 0.57 mmol) and(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 137 mg, 0.57 mmol) in DCM (4 mL), at RT and under anitrogen atmosphere, sodium triacetoxyborohydride (181 mg, 0.86 mmol)was added portion-wise and the resulting reaction mixture was stirredovernight. A solution of concentrated ammonium chloride was added, themixture was diluted with DCM, and the organic phase was washed withwater, dried over sodium sulfate and the solvent removed under vacuum.The crude material was purified by aminic FC (eluting with DCM/MeOH from100/0 to 95/5) to give(1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E296, 85 mg, y=32%). NMR: ¹H NMR (CDCl₃) δ: 7.53 (d, 2H),7.15-7.21 (m, 2H), 4.07-4.17 (m, 2H), 3.52-3.59 (m, 2H), 3.51 (s, 3H),2.84-2.96 (m, 1H), 2.75 (d, 4H), 2.55-2.66 (m, 2H), 2.47-2.55 (m, 2H),2.05-2.17 (m, 4H), 1.84 (br. s., 4H), 1.59-1.74 (m, 3H), 1.45-1.56 (m,1H), 1.22-1.29 (m, 1H), 1.08-1.15 (m, 1H). MS (m/z): 463.5 [MH]⁺.

Example 297 and Example 298: (1S,3S or1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E297, Enantiomer 1) and (1R,3R or1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E298, Enantiomer 2)

(1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E296, 85 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5 um Mobile phasen-Hexane/(2-Propanol/Methanol 1/1 + 0.1% isopropylamine) 80/20 v/v Flowrate (ml/min) 18 ml/min DAD detection 220 nm Loop 1000 μL Injection 10mg/injection

affording (1S,3S or1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E297, 24 mg), Enantiomer 1: ret. time 9.5 min. MS (m/z): 463.5[MH]⁺ and (1R,3R or1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E298, 23 mg), Enantiomer 2: ret. time 12.1 min. MS (m/z): 463.5[MH]⁺.

Example 299: (1S,3S or1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E299, Enantiomer 1)

(1S,3S or1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E297, 24 mg) was dissolved in DCM and treated with 1.1 eq of HCl2N in Et₂O affording (1S,3S or1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 1, E299, 25 mg). MS (m/z): 463.5[MH]⁺.

Example 300: (1R,3R or1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (TRANS, E300, Enantiomer 2)

(1R,3R or1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E298, 23 mg) was dissolved in DCM and treated with 1.1 eq of HCl2N in Et₂O affording (1R,3R or1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloric salt (TRANS, Enantiomer 2, E300, 24 mg). MS (m/z): 463.5[MH]⁺.

Example 301:(1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, E301)

Step a: To a solution of4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole(p248, 62 mg, 0.27 mmol) in THF/H₂O (2.3/0.5 mL) were subsequently addedOsO₄ (0.10 mL, 4% solution in water, 0.014 mmol) and NalO₄ (173 mg, 0.81mmol). The reaction mixture was stirred overnight at RT. Water was addedand the mixture was extracted with DCM. The organic phase was dried oversodium sulfate and the solvent removed under vacuum affording4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal(35 mg) as colorless oil that was used as such in the next step.

Step b: In a vial a solution of4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal(33 mg, from step a) and(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 44 mg, 0.18 mmol) in DCM (0.5 mL) was shaken for 10 min at RT.Na(AcO)₃BH (45 mg, 0.21 mmol) was added portion-wise and the resultingreaction mixture was shaken overnight at RT in a PLS apparatus. Themixture was diluted with DCM and washed with concentrated sodiumbicarbonate solution. The organic phase was dried over sodium sulfateand the solvent removed under vacuum. The residue was purified by FC onsilica (eluting with DCM/MeOH from 100/0 to 90/10) then further purifiedby aminic FC (eluting with EA/MeOH from 100/0 to 97/3) affording(1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(16 mg).

Step c:(1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(16 mg) was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.019 mL, 0.038mmol) was added and the reaction mixture was concentrated under vacuum.The solid so obtained was triturated with ether and dried under vacuumat 45° C. overnight affording(1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, E301, 17 mg, y=19%) as pale yellow foam. NMR: ¹H NMR(DMSO-d₆) δ: 10.11-10.46 (m, 1H), 8.54 (s, 1H), 7.68 (d, 2H), 7.45 (d,2H), 3.61-3.71 (m, 4H), 3.20 (br. s., 5H), 2.55-2.87 (m, 4H), 2.31-2.44(m, 3H), 2.24 (m, 1H), 2.03-2.15 (m, 1H), 1.71 (d, 4H), 1.26-1.54 (m,2H). MS (m/z): 460.5 [MH]⁺.

Example 302:(1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl})-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E302)

Step a: To a solution of4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole(p248, 107 mg, 0.46 mmol) in THF/H₂O (4 mL/00.8 mL) were subsequentlyadded OsO₄ (0.15 mL, 4% solution in water, 0.023 mmol) and NalO₄ (295mg, 1.38 mmol). The reaction mixture was stirred overnight at RT. Waterwas added and the mixture was extracted with DCM. The organic phase wasdried over sodium sulfate and the solvent removed under vacuum affording4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal(107 mg) that was used as crude in the next step.

Step b: In a vial a solution of4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal(53 mg, from step a) and(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p15, 40 mg, 0.17 mmol) in DCM (0.6 mL) was shaken for 10min at RT. Na(AcO)₃BH (73 mg, 0.35 mmol) was added portion-wise and theresulting reaction mixture was shaken O/N at RT in a PLS apparatus. Themixture was diluted with DCM and washed with concentrated sodiumbicarbonate solution. The organic phase was dried over sodium sulfateand the solvent removed under vacuum. The residue was purified by FC onNH column (eluting with EA/MeOH from 100/0 to 97/3) to give(1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(29 mg).

Step c:(1R,3S)-5-{4-[4-methyl-5-(4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(29 mg) was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.035 mL) wasadded and the reaction mixture was concentrated under vacuum. The solidso obtained was triturated with ether and dried under vacuum at 45° C.overnight affording(1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanehydrochloride (CIS, Enantiomer 1, E302, 31 mg, y=37%) as white solid.NMR: ¹H NMR (DMSO-d₆) δ: 10.26-10.57 (m, 1H), 8.55 (s, 1H), 7.68 (d,2H), 7.45 (d, 2H), 3.64 (s, 3H), 2.88-3.42 (m, 6H), 2.37-2.86 (m, 4H),2.35 (s, 3H), 2.03-2.30 (m, 2H), 1.71 (d, 4H), 1.27-1.53 (m, 2H). MS(m/z): 460.4 [MH]⁺.

Preparation 261:(1S,3S/1R,3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS)

A mixture of(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p13, 100 mg, 0.41 mmol),(3-bromopropoxy)(tert-butyl)dimethylsilane (0.143 mL, 0.615 mmol), TEA(0.171 mL, 1.23 mmol), NaI (12 mg, 0.082 mmol) in DMF (2 mL) was stirredat 50° C. O/N. The mixture was then diluted with brine and DCM, phaseswere separated and the aqueous one was extracted twice with DCM.Combined organics were dried and concentrated under reduced pressure.Crude material was purified by FC on NH column (eluent: Cy to EtoAC 20%)affording(1S,3S/1R,3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p261, 73 mg, y=44%) as colourless oil. MS (m/z): 414.6 [MH]⁺

Preparation 262:3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propan-1-ol(TRANS)

(1S,3S/1R,3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, p261, 73 mg, 0.18 mmol) was dissolved in THF (1 mL) and treatedwith HCl 1M (1 mL). The mixture was left stirring at RT for 1 h. NaOH 1Mwas then added to bring pH to 8 and the mixture was extracted withEtOAc. NaOH 1M was added till pH 10 and the acqueous phase was extractedagain with DCM. Combined organics were dried and concentrated to obtain3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propan-1-ol(TRANS, p262, 49 mg, y=84%) as colourless oil. MS (m/z): 300.3 [MH]⁺.

Preparation 263:4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole

To a solution of 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole-3-thiol (p66,500 mg, 2.5 mmol) in EtOH (3.75 mL) iodomethane (187 uL, 3 mmol) wasadded dropwise. The resulting mixture was stirred at 80° C. for 30′.Solvent was evaporated in vacuum; the residue was dissolved in NaOH 1Mand extracted three times with DCM. Combined organics were dried andconcentrated to obtain4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole (p263, 482mg, y=90%) as white solid. MS (m/z): 214.2 [MH]⁺

Preparation 264:3-methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole

To a solution of4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole (p263, 482mg, 2.26 mmol) in DCM (6 mL) 3-chloro perbenzoic acid (1.17 g, 6.78mmol) was added portionwise. The resulting mixture was stirred at RT for3 hrs. EtOAc was then added till complete dissolution, followed byNaHCO₃ ss. Phases were separated and the aqueous one was backextractedonce with EtOAc, then several times with DCM. Combined organics weredried and concentrated to give3-methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p264, 412mg, y=71%) as white solid. MS (m/z): 246.2 [MH]⁺.

Example 303:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E303)

To a solution of3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propan-1-ol(TRANS, p262, 49 mg, 0.16 mmol) in DMF (1.5 mL),3-methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p264, 39 mg,0.16 mmol) was added followed by NaH 60% in mineral oil (9.6 mg, 0.24mmol) and the mixture was shaken in a PLS apparatus at 60° C. for 4 hrs.Further NaH was added (52 mg in 5 subsequent additions) and the mixturewas shaken for overall 26 hrs. The reaction was cooled down to 0° C.with an ice bath and water was slowly added. The mixture was extractedthree times with DCM, then twice with EtOAc. Combined organics weredried and concentrated; crude material was purified by FC on silica gel(eluent: DCM to DCM/MeOH 0:10) to obtain(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E303, 49 mg, y=58%) as colourless gum. NMR: ¹H NMR (Acetone-d₆)δ: 7.62 (d, 2H), 7.34 (d, 2H), 4.40-4.49 (m, 2H), 3.91-4.02 (m, 2H),3.44-3.54 (m, 2H), 3.40 (s, 3H), 2.90-3.01 (m, 1H), 2.72-2.76 (m, 2H),2.53-2.66 (m, 5H), 2.18-2.30 (m, 1H), 1.94-2.02 (m, 2H), 1.81-1.86 (m,3H), 1.61-1.70 (m, 1H), 1.37-1.46 (m, 1H), 1.25 (d, 1H), 1.20 (s, 1H).MS (m/z): 481.1 [MH]⁺.

Example 304 and Example 305: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E304, Enantiomer 1) and (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E305, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E303, 49 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 90/10% v/v Flowrate (ml/min) 18 ml/min DAD detection 220 nm Loop 600 μL Injection 13.3mg/injection

affording (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E304, 14 mg). Enantiomer 1: ret. time 16.1 min, 100% ee. MS(m/z): 465.5 [MH]⁺ and (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(TRANS, E305, 11 mg). Enantiomer 2: ret. time 19.4 min, 100% ee. MS(m/z): 465.5 [MH]⁺.

Preparation 265: Benzyl-Triphenyl-Phosphonium Bromide

A solution of PPh₃ (7.66 g, 29.23 mmol) and benzyl bromide (3.48 mL,29.23 mmol) in toluene (70 mL) was refluxed O/N; the mixture was thenallowed to cool down to RT and the resulting precipitate was collectedby filtration, washed with pentane and dried in vacuo to affordbenzyl-triphenyl-phosphonium bromide (p265, 12 g, y=95%) as white solid.MS (m/z): 353.2 [M-Br]⁺

Preparation 266: tert-butyl4-(phenylmethylidene)piperidine-1-carboxylate

A suspension of benzyl-triphenyl-phosphonium bromide (p265, 10.87 g,25.09 mmol) in THF (70 mL) was cooled with ice bath, then NaH 60%dispersion in mineral oil (1.1 g, 27.6 mmol) was added. The suspensionwas stirred at 0° C. for 10 min then at RT for 45 min, the suspensionbecame orange-yellow.

Tert-butyl 4-oxo-1-piperidinecarboxylate (5 g, 25.09 mmol) dissolved inTHF (30 mL) was added dropwise and the resulting reaction mixture wasstirred at RT O/N. The mixture was then cooled down to 0° C. and dilutedwith water and EtOAc. The organic phase was separated and washed withNaHCO₃ ss, then dried and evaporated. The reasidual oil was treated withEt₂O in order to precipitate the triphenylphosphoxide that was filteredoff. The solution was evaporated and the residue was purified by FC onsilica gel (eluent from cHex to 10% EtOAc) to afford the title compoundtert-butyl 4-(phenylmethylidene)piperidine-1-carboxylate (p266, 5.46 g,y=79%) as white solid. MS (m/z): 274.2 [MH]⁺.

Preparation 267: tert-butyl(2R/2S)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6-carboxylate

Tetrabutylammonium bromide (150 mg, 0.46 mmol) was added to a mixture oftert-butyl 4-(phenylmethylidene)piperidine-1-carboxylate (p266, 3 g,10.97 mmol) in CHCl₃ (50 mL) and 50% aqueous NaOH (10 mL). The reactionmixture was stirred at RT for 3 hrs, then further 30 mL of 50% aqueousNaOH were added. After 48 hrs the reaction mixture was diluted with DCMand washed with water. The aqueous layer was extracted with DCM and thecombined organics were dried and concentrated. The residue was purifiedby FC on silica gel (eluting from cHex to 10% EtOAc) to affordtert-butyl(2R/2S)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6-carboxylate (p267,4 g, y=quant) as colourless oil. MS (m/z): 356.2 [MH]⁺

Preparation 268: (2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane

To a stirred solution of tert-butyl(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6-carboxylate (p267,2 g, 5.6 mmol) in DCM (20 mL), TFA (4 mL) was added and the resultingsolution was left stirring at RT for 1 h. Solvent was removed in vacuumand the residue was loaded on a SCX cartridge eluting with 1M NH₃ inMeOH to afford the title compound(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane (p268, 1.3 g) aspale yellow oil that was used as such in the next step. MS (m/z): 256.2[M]⁺.

Preparation 269:1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octan-6-yl]-2,2,2-trifluoroethan-1-one

To a stirred solution of(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane (p268, 450 mg, 1.75mmol) in DCM (10 mL) Trifluoroacetic acid anhydride (0.364 mL) was addedand the resulting solution was left stirring at RT O/N. It was thendiluted with further DCM and washed with 1N NaOH. The organic solventwas dried and evaporated. The residue was purified by FC on silica gel(eluting from cHex to 10% EtOAc) to afford1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octan-6-yl]-2,2,2-trifluoroethan-1-one(p269, 550 mg, y=89%) as white solid. MS (m/z): 352.1 [M]⁺.

Preparation 270:2,2,2-trifluoro-1-[(1R/1S)-1-phenyl-6-azaspiro[2.5]octan-6-yl]ethan-1-one

To a stirred solution of1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octan-6-yl]-2,2,2-trifluoroethan-1-one(p269, 550 mg, 1.56 mmol) in EtOH/H₂O (10 mL/1 mL), Zn powder (560 mg,8.58 mmol) was added. The resulting mixture was left stirring at refluxO/N. Solid was filtered off and washed with MeOH. The solution wasconcentrated and the residue was purified by FC on silica gel (elutingfrom cHex to 10% EtOAc) to afford the title compound2,2,2-trifluoro-1-[(1R/1S)-1-phenyl-6-azaspiro[2.5]octan-6-yl]ethan-1-one(p270, 130 mg, y=29%) as colourless oil. MS (m/z): 284.2 [MH]⁺.

Preparation 271: (1R/1S)-1-phenyl-6-azaspiro[2.5]octane

To a stirred solution of2,2,2-trifluoro-1-{1-phenyl-6-azaspiro[2.5]octan-6-yl}ethan-1-one (p270,130 mg, 0.46 mmol) in MeOH/H₂O (4 mL/2 mL), K₂CO₃ (127 mg, 0.92 mmol)was added. The resulting solution was left stirring at RT for 1 h. MeOHwas evaporated, then DCM and 1N NaOH were added and the product wasextracted several times with DCM. The organic phase was dried andevaporated to afford (1R/1S)-1-phenyl-6-azaspiro[2.5]octane (p271, 100mg, 70% pure) as colourless oil that was used as such in the next step.MS (m/z): 188.2 [MH]⁺.

Example 306:(1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E306)

The compound was prepared as in Example 1, reacting(1R/1S)-1-phenyl-6-azaspiro[2.5]octane (p271, 50 mg, 0.267 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 80 mg, 0.29 mmol), Na₂CO₃ (34 mg, 0.32 mmol) and NaI (48 mg, 0.32mmol) in DMF (0.2 mL) affording the title compound(1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E306, 53 mg, y=48%). NMR: ¹H NMR (Acetone-d₆) δ: 8.28 (s, 1H),7.12-7.34 (m, 5H), 3.75-3.86 (m, 3H), 3.30 (m, 2H), 2.45-2.70 (m, 4H),2.43 (s, 3H), 2.18-2.39 (m, 2H), 1.93-2.04 (m, 3H), 1.49-1.73 (m, 2H),1.18-1.36 (m, 2H), 0.96-1.03 (m, 1H), 0.78-0.86 (m, 1H). MS (m/z): 424.1[MH]⁺.

Example 307 and Example 308: (1S or1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E307, Enantiomer 1) and (1R or1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E308, Enantiomer 2)

(1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E306, 44 mg) was separated into the single enantiomers by preparativechiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2 cm), 5 um Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 20/80 v/v Flowrate (ml/min) 20 ml/min DAD detection 220 nm Loop 2000 μL Injection 44mg/injection

affording (1S or1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E307, 18 mg), Enantiomer 1: ret. time 9.0 min, 100% ee, MS (m/z): 424.5[MH]⁺ and (1R or1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane(E308, 19 mg), Enantiomer 2: ret. time 14.9 min, 100% ee. MS (m/z):424.5 [MH]⁺.

Example 309: (1S or1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octanehydrochloride (E309, Enantiomer 1)

(1S or1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-phenyl-6-azaspiro[2.5]octane(E307, 18 mg) was treated with 1.1 eq of HCl in Et₂O affording (1S or1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octanehydrochloric salt (Enantiomer 1, E309, 18.6 mg). MS (m/z): 424.1 [MH]⁺.

Preparation 272: N-benzyl-2-chloroacetamide

2-chloroacetyl chloride (0.796 mL, 10 mmol) was slowly added dropwise toa mixture of benzylamine (0.906 mL, 8.3 mmol) and TEA (1.4 mL, 10 mmol)in anhydrous DCM (8 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 4 hrs. The reaction mixture was washed withNaHCO₃, NH₄Cl and Brine. Organic phase was separated, dried over Na₂SO₄and concentrated to obtain N-benzyl-2-chloroacetamide (p272, 1.58 g,y=98%) as grey solid. MS (m/z): 184.1 [MH]⁺.

Preparation 273: [(benzyl carbamoyl)methyl]triphenylphosphanium chloride

To a solution of N-benzyl-2-chloroacetamide (p272, 1.58 g, 8.17 mmol) inToluene (10 mL) Triphenylphosphine (2.25 g, 8.58 mmol) was added and thereaction was stirred at reflux (110° C.) O/N. A precipitate formed. Thereaction was cooled to RT, Et₂O was added and the suspension wasfiltered. The brown solid was washed with Et₂O and dried under highvacuum to obtain [(benzylcarbamoyl)methyl]triphenylphosphanium chloride(p273, 3.26 g, y=83%). MS (m/z): 410.4 [MH]⁺.

Preparation 274: 1-benzyl-3-methylidenepiperidine-2,6-dione

Step a: To a solution of [(benzylcarbamoyl)methyl]triphenylphosphaniumchloride (p273, 2.76 g, 6.15 mmol) in MeOH (44 mL) at 0° C.methoxysodium (831 mg, 15.38 mmol) was added and the reaction wasstirred at 0° C. for 10′. Then the ice bath was removed and methylacrylate (0.553 mL, 6.15 mmol) was added and the reaction was stirred atRT O/N. The day after the reaction was concentrated and the residue wasdissolved in DCM and washed with water. Organic phase was dried overNa₂SO₄ and concentrated to obtain1-benzyl-3-(triphenyl-λ⁵-phosphanylidene)piperidine-2,6-dione (2.91 g)as brown oil that was used as crude in the next step.

Step b: To a solution of1-benzyl-3-(triphenyl-λ⁵-phosphanylidene)piperidine-2,6-dione (2.91 g,6.28 mmol) in Toluene (60 mL), formaldehyde 37% in water (0.374 mL, 5.02mmol) was added and the reaction was stirred at RT for 2 hrs. EtOAc andwater were added, phases were separated, acqueous one was extractedtwice with EtOAc. Combined organics were dried over Na₂SO₄ andconcentrated. Crude material was purified by FC on silica gel (eluentfrom Cy to EtOAc 30%) to obtain1-benzyl-3-methylidenepiperidine-2,6-dione (p274, 400 mg, y=30%) asyellow oil. MS (m/z): 216.2 [MH]⁺.

Preparation 275 and 276:(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(TRANS, p275) and(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(CIS, p276)

To a solution of {[4-(trifluoromethyl)phenyl]methylidene}hydrazine (p1,350 mg, 1.86 mmol) in dioxane (4 mL) at 10° C., MnO₂ (1.62 g, 50 mmol)was added portionwise. The resulting mixture was stirred at RT for 30min, then it was filtered over a pad of Celite washing with dioxane andthis solution was added to a solution of1-benzyl-3-methylidenepiperidine-2,6-dione (p274, 400 mg, 1.86 mmol) indioxane (1.4 mL). The resulting orange solution was left stirring at RTO/N. Solvent was removed and crude material was purified by FC on silicacartridge (eluting from cHex to 30% EtOAc) to afford:

(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(TRANS, p275, 347 mg, y=45%) as colourless gum and(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(CIS, p276, 186 mg, y=21%) as wax. MS (m/z): 374.3 [MH]⁺.

Preparation 277:(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS)

(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(TRANS, p275, 347 mg, 0.93 mmol) was dissolved in THF (5 mL) and LiAlH₄1M in THF (1.86 mL, 1.86 mmol) was added dropwise. The resulting orangesolution was heated at reflux (70° C.) for 1 h. Then it was cooled withan ice bath and quenched with Na₂SO₄ 10*H₂O until gas evolution ceased.It was filtered over a pad of celite washing with EtOAc, the solutionwas concentrated to afford(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, p277, 260 mg, y=60%) as yellow oil that was used as such in thenext step. MS (m/z): 346.4 [MH]⁺.

Preparation 278:(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS)

(1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, p277, 260 mg, 0.75 mmol) was dissolved in MeOH (3 mL) under N₂and Ammonium formate (236 mg, 3.75 mmol) was added followed by Pd/C (25mg). The resulting mixture was stirred at reflux for 1.5 h.

After cooling, it was filtered over a pad of Celite, the solvent wasevaporated and the residue was partitioned between DCM and NaHCO₃(aqueous phase with pH ˜8) and washed three times with DCM. Organiclayers were combined, dried over a Phase Separator and concentrated.Crude material was purified with C18 cartridge (eluent from Water to ACN30%). Fractions containing the product were combined and volatiles wereevaporated. The remaining water was basified and extracted several timeswith DCM. Combined organics were dried over Na₂SO₄ and concentrated toobtain (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, p278, 50 mg, y=26%) as yellow oil. MS (m/z): 256.1 [MH]⁺.

Preparation 279:(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS)

(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione(CIS, p276, 186 mg, 0.5 mmol) was dissolved in THF (3 mL) and LiAlH₄ 1Min THF (1 mL, 1 mmol) was added dropwise. The resulting orange solutionwas heated at reflux (70° C.) for 1 h. Then it was cooled with an icebath and quenched with Na₂SO₄ 10*H₂O until gas evolution ceased. It wasfiltered over a pad of celite washing with EtOAc, the solution wasconcentrated to afford(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, p279, 153 mg, y=62%) as yellow oil that was used as such in thenext step. MS (m/z): 346.4 [MH]⁺.

Preparation 280:(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS)

(1S,3S/1R,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, p279, 153 mg, 0.44 mmol) was dissolved in MeOH (2 mL) under N₂ andammonium formate (138 mg, 2.2 mmol) was added followed by Pd/C (15 mg).The resulting mixture was stirred at reflux for 1.5 h.

After cooling, it was filtered over a pad of Celite, the solvent wasevaporated and the residue was partitioned between DCM and NaHCO₃(aqueous phase with pH ˜7) and washed three times with DCM. Organiclayers were combined, dried and concentrated. Crude material waspurified with C18 cartridge (eluent from Water to ACN 30%) then furtherpurified by FC on silica cartridge (eluent from DCM to MeOH) to obtain(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS,p280, 47 mg, y=36%) as white solid. MS (m/z): 256.1 [MH]⁺.

Example 310:(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E310)

The compound was prepared as in Example 1, reacting(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, p278, 49 mg, 0.19 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 57 mg, 0.21 mmol), Na₂CO₃ (24 mg, 0.228 mmol) and NaI (34 mg,0.228 mmol) in DMF (0.2 mL) affording(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E310, 33 mg, y=34%). NMR: ¹H NMR (Acetone-d₆) δ: 8.25-8.29 (m,1H), 7.59-7.64 (m, 2H), 7.43-7.52 (m, 2H), 3.81 (s, 3H), 3.31-3.47 (m,2H), 2.44-2.55 (m, 3H), 2.42 (s, 3H), 2.25-2.39 (m, 3H), 2.14-2.22 (m,1H), 1.95-2.03 (m, 2H), 1.15-1.48 (m, 4H), 0.93-1.14 (m, 3H). MS (m/z):492.3 [MH]⁺.

Example 311 and Example 312: (1R,3S or1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E311, Enantiomer 1) and (1S,3R or1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E312, Enantiomer 2)

(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E310, 33 mg) was separated into the single enantiomers bypreparative chiral HPLC (SFC).

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Modifier (Ethanol + 0.1%isopropylamine) 5% for 25 min −> 8% Flow rate (ml/min) 45 ml/minPressure (bar) 120 Temperature (° C.) 38 DAD detection 220 nm Loop 500μL Injection 5 mg/injection

affording (1R,3S or1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E311, 10 mg), Enantiomer 1: ret. time 17.7 min, 100% ee. MS(m/z): 492.4 [MH]⁺ and (1S,3R or1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(TRANS, E312, 10 mg). Enantiomer 2: ret. time 20.6 min, 100% ee. MS(m/z): 492.5 [MH]⁺.

Example 313:(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E313)

The compound was prepared as in Example 1, reacting(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS,p280, 46 mg, 0.18 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 54 mg, 0.198 mmol), Na₂CO₃ (23 mg, 0.216 mmol) and NaI (32 mg,0.216 mmol) in DMF (0.2 mL) affording(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E313, 23 mg, y=25%). NMR: ¹H NMR (Acetone-d₆) δ: 8.27 (s, 1H),7.62 (d, 2H), 7.48 (br. s., 2H), 3.81 (s, 3H), 3.40 (br. s., 2H), 2.48(br. s., 3H), 2.42 (s, 3H), 2.34 (br. s., 3H), 2.21 (br. s., 1H), 1.97(br. s., 2H), 1.16-1.49 (m, 4H), 0.94-1.15 (m, 3H). MS (m/z): 492.5[MH]⁺.

Example 314 and Example 315: (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E314, Enantiomer 1) and (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E315, Enantiomer 2)

(1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E313, 23 mg) was separated into the single enantiomers bypreparative chiral HPLC.

Preparative Chromatography:

Column Chiralcel OJ-H (25 × 2.0 cm), 5μ Mobile phasen-Hexane/(Ethanol/Methanol 1/1 + 0.1% isopropylamine) 75/25% v/v Flowrate (ml/min) 17 ml/min DAD detection 220 nm Loop 1000 μL Injection 10.5mg/injection

affording (1S,3S or1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E314, 9.6 mg). Enantiomer 1: ret. time 7.1 min, 100% ee. MS (m/z):492.5 [MH]⁺ and (1R,3R or1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane(CIS, E315, 7.9 mg). Enantiomer 2: ret. time 8.5 min, 100% ee. MS (m/z):492.4 [MH]⁺.

Preparation 281: 3-chloro-1-phenylpropan-1-ol

To a stirred solution of 3-chloro-1-phenylpropan-1-one (7.80 g, 46.26mmol) in THF (35 mL) and EtOH (35 mL), at −10° C. and under a nitrogenatmosphere, sodium borohydride (2.20 g, 48.83 mmol) was addedportion-wise over 10 min. The reaction mixture was stirred foradditional 10 min at −5° C. then cautiously poured into a stirredmixture of saturated ammonium chloride (85 mL) and ice (40 g). Themixture was extracted with ether twice, the organic phase was dried andthe solvent removed under reduced pressure. The crude material waspurified by FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) togive the title compound 3-chloro-1-phenylpropan-1-ol (p281, 7.50 g,y=95%) as pale yellow oil. NMR: ¹H NMR (CDCl₃) δ: 7.39 (d, 5H),4.91-5.01 (m, 1H), 3.70-3.83 (m, 1H), 3.59 (s, 1H), 2.20-2.32 (m, 1H),2.11 (d, 1H)

Preparation 282: (1-bromo-3-chloropropyl)benzene

A mixture of 3-chloro-1-phenylpropan-1-ol (p281, 7.50 g, 43.95 mmol) and48% aqueous hydrobromic acid (98 mL) was stirred at RT for 3 hrs, thencautiously poured into a mixture of potassium carbonate (27 g) and 180 gof ice. Potassium carbonate was cautiously added up to neutral pH. Theresulting mixture was extracted twice with ether, the organic phase wasdried and the solvent removed under vacuum. The crude material waspurified by FC on silica gel (eluting with Cy) affording(1-bromo-3-chloropropyl)benzene (p282, 7.49 g, y=73%) as colourless oil.NMR: ¹H NMR (CDCl₃) δ: 7.32-7.50 (m, 5H), 5.24 (m, 1H), 3.75 (m, 1H),3.61 (m, 1H), 2.67-2.80 (m, 1H), 2.45-2.58 (m, 1H)

Preparation 283: 1,1-dimethyl 2-phenylcyclobutane-1,1-dicarboxylate

A stirred solution of (1-bromo-3-chloropropyl)benzene (p282, 4.78 g,20.47 mmol) and dimethyl malonate (2.97 g, 22.52 mmol) in anhydrousdioxane (60 mL) and under a nitrogen atmosphere, was brought to 90° C.,then 60% NaH (0.86 g, 21.49 mmol) was cautiously added portion-wise over10 min and the reaction was heated to reflux. After 1 h, the reactiontemperature was allowed to reach about 90° C. and additional 60% NaH(0.86 g, 21.49 mmol) was added portion-wise over 10 min and the reactionmixture was brought to reflux and stirred overnight. After allowing themixture to reach RT, it was filtered, the solid was washed with etherand the filtrate was concentrated under reduced pressure. The crudematerial was purified by FC on silica gel (eluting with Cy/EA from 100/0to 93/7) then further purified inverse FC (C18, eluting with MeCN+0.1%formic acid/water+0.1% formic acid from 0/100 to 70/30) affording1,1-dimethyl 2-phenylcyclobutane-1,1-dicarboxylate (p283, 2.36 g, y=45%)as colourless oil. NMR: ¹H NMR (CDCl₃) δ: 7.22-7.33 (m, 5H), 4.39 (m,1H), 3.80 (s, 3H), 3.26 (s, 3H), 2.59-2.76 (m, 2H), 2.16-2.34 (m, 2H)

Preparation 284: methyl 2-phenylcyclobutane-1-carboxylate

A stirred mixture of 1,1-dimethyl 2-phenylcyclobutane-1,1-dicarboxylate(p283, 2.17 g, 8.74 mmol), LiCl (0.79 g, 18.62 mmol) and water (0.17 mL)in DMSO (12 mL) was brought to reflux and stirred for 1.5 h. Aftercooling to RT, this mixture was diluted with ether (55 mL) andcyclohexane (23 mL) then was washed sequentially with brine, water (3times) and brine. The organic phase was dried and the solvent wasremoved under reduced pressure. The residue was purified by FC on silicagel (eluting with Cy/EA from 100/0 to 97/3) to give methyl2-phenylcyclobutane-1-carboxylate (p284, 1.07 g, y=64%) as colourlessoil. MS (m/z): 191.2 [MH]⁺.

Preparation 285: methyl2-phenyl-1-(prop-2-en-1-yl)cyclobutane-1-carboxylate

To a solution of methyl 2-phenylcyclobutane-1-carboxylate (p284, 1.07 g,5.62 mmol) in THF (14 mL) at −78° C. under N₂, 1M/THF LHMDS (7.3 mL,7.30 mmol) was added dropwise and the reaction was stirred at thistemperature for 30′. Then allyl bromide (0.73 mL, 8.44 mmol) was addeddropwise and the reaction was allowed to reach RT and stirred overnight.The reaction mixture was treated with aqueous saturated NH₄Cl anddiluted with EA. The organic phase was washed with water, dried and thesolvent removed under reduced pressure. The crude material was purifiedby FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) affordingmethyl 2-phenyl-1-(prop-2-en-1-yl)cyclobutane-1-carboxylate (p285, 0.71g, y=55%) as pale yellow oil. MS (m/z): 232.2 [MH]⁺.

Preparation 286: methyl 1-(2-oxoethyl)-2-phenylcyclobutane-1-carboxylate

A slow stream of O₃ in O₂ was passed through a −78° C. cooled solutionof methyl 2-phenyl-1-(prop-2-en-1-yl)cyclobutane-1-carboxylate (p285,0.71 g, 3.08 mmol) in DCM (10 mL) until a pale blue color persisted (30min). Excess of O₃ was purged by nitrogen bubbling, and then a solutionof TPP (0.89 g, 3.39 mmol) in DCM (2 mL) was added. The solution wasallowed to reach 25° C. and it was stirred for 2 hrs. The solvent wasremoved in vacuo and the crude material was purified by FC on silica gel(eluting with Cy/EA from 100/0 to 70/30) to give methyl1-(2-oxoethyl)-2-phenylcyclobutane-1-carboxylate (p286, 0.36 g, y=51%)as colorless oil. MS (m/z): 233.2 [MH]⁺.

Preparation 287: 6-benzyl-1-phenyl-6-azaspiro[3.4]octan-5-one

To a solution of methyl 1-(2-oxoethyl)-2-phenylcyclobutane-1-carboxylate(p286, 360 mg, 1.55 mmol) and benzylamine (0.18 mL, 1.63 mmol) in THF(9.0 mL) was added sodium triacetoxyborohydride (493 mg, 2.33 mmol). Thereaction mixture was stirred at RT O/N and then quenched with saturatedaqueous NaHCO₃. The mixture was extracted with DCM twice, the organicphase was dried and the solvent removed under reduced pressure. Theresidue was dissolved in THF (30 mL) and the resulting solution wasrefluxed for 8 h. The reaction mixture was concentrated under vacuum andthe residue was purified by FC on NH column (eluting with Cy/EA from100/0 to 70/30) then loaded on a SCX cartridge (washing with MeOH andeluting with 2N NH₃/MeOH) affording6-benzyl-1-phenyl-6-azaspiro[3.4]octan-5-one (p287, 124 mg, y=27%) aswhite foam. MS (m/z): 292.3 [MH]⁺.

Preparation 288: 6-benzyl-1-phenyl-6-azaspiro[3.4]octane

To a stirred solution of 6-benzyl-1-phenyl-6-azaspiro[3.4]octan-5-one(p287, 124 mg, 0.43 mmol) in THF (4 mL), at 0° C. and under a nitrogenatmosphere, 1M/THF LiAlH₄ (0.55 mL, 0.55 mmol) was added drop-wise. Theice-bath was removed and the resulting reaction mixture was allowed toreach RT then refluxed for 1 h. The mixture was then cooled to 0° C. andquenched with Na₂SO_(4*)10H₂O, diluted with EA, filtered over sodiumsulphate and the solvent was removed under vacuum to give6-benzyl-1-phenyl-6-azaspiro[3.4]octane (p288, 120 mg, y=quant.) thatwas used as such in the next step. MS (m/z): 278.3 [MH]⁺.

Preparation 289: 1-phenyl-6-azaspiro[3.4]octane

To a solution of 6-benzyl-1-phenyl-6-azaspiro[3.4]octane (p288, 120 mg,0.43 mmol) in MeOH (5 mL), HCOONH₄ (164 mg, 2.60 mmol) and 10% Pd/C (52mg) were added at RT then the mixture was stirred at reflux for 2 hrs.The reaction mixture was filtered over a pad of celite and the solventremoved under vacuum. The residue was dissolved in DCM, the solutionwashed with saturated sodium bicarbonate, dried and the solvent removedunder vacuum. The residue was dissolved in MeOH and the solution wasloaded on a SCX cartridge (washing with MeOH and eluting with 2N/NH₃ inMeOH) affording 1-phenyl-6-azaspiro[3.4]octane (p289, 63 mg, y=78%) ascolorless oil. MS (m/z): 188.2 [MH]⁺.

Example 316:6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane(E316)

The compound was prepared as in Example 1, reacting1-phenyl-6-azaspiro[3.4]octane (p289, 58 mg, 0.31 mmol),3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p148, 93 mg, 0.34 mmol), Na₂CO₃ (40 mg, 0.37 mmol) and NaI (51 mg, 0.34mmol) in DMF (0.35 mL) affording the title compound6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane(E316, 67 mg, y=51%) as diastereoisomeric mixture. NMR: ¹H NMR (CDCl₃)δ: 7.95 (s, 1H), 7.30-7.38 (m, 2H), 7.18-7.26 (m, 3H), 3.67-3.72 (s,3H), 3.54 (m, 1H), 3.08-3.20 (m, 2H), 2.65-2.97 (m, 2H), 2.55 (s, 3H),2.51 (d, 2H), 2.31-2.41 (m, 1H), 2.02-2.30 (m, 7H), 1.94 (d, 2H). MS(m/z): 424.4 [MH]⁺.

Example 317, Example 318, Example 319 and Example 320: (1R,4S or 1S,4Ror 1S,4S or1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane:E317 (Diastereomer 1 Enantiomer 1); E318 (Diastereomer 1 Enantiomer 2);E319 (Diastereomer 2 Enantiomer 1); E320 (Diastereomer 2 Enantiomer 2)

6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane(E316, 66 mg) was separated into the single enantiomers of eachdiastereomer by preparative chiral HPLC.

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.0 cm), 5μ Mobile phase Ethanol + 0.1%isopropylamine 20% Flow rate (ml/min) 45 ml/min DAD detection 220 nmLoop 500 μL Injection 11 mg/injection

affording 18 mg E317 (Diastereomer 1 Enantiomer 1): ret. time 10.1 min,98.2% ee, MS (m/z): 424.4 [MH]⁺ and 23 mg E318 (Diastereomer 1Enantiomer 2): ret. time 11.9 min, 98.2% ee, MS (m/z): 424.4 [MH]⁺ and2.3 mg E319 (Diastereomer 2 Enantiomer 1): ret. time 16.7 min, 100% ee,MS (m/z): 424.4 [MH]⁺ and 2 mg E320 (Diastereomer 2 Enantiomer 2): ret.time 21 min, 100% ee, MS (m/z): 424.4 [MH]⁺.

Example 321: (1R,4S or 1S,4R or 1S,4S or1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octanehydrochloride (E321, Diastereomer 1 Enantiomer 2)

(1R,4S or 1S,4R or 1S,4S or1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane(E318, Diastereomer 1 Enantiomer 2, 23 mg) was treated with 1.1 eq ofHCl in Et₂O affording the corresponding hydrochloric salt (E321,Diastereomer 1 Enantiomer 2, 24 mg). MS (m/z): 424.4 [MH]⁺.

Biological Test Methods

[³H]-Spiperone Binding Assay at hD₃ and hD₄ recombinant receptors. CHOcells transiently transfected with human dopamine type 3 or 4 receptors(CHO-hD₃ or CHO-hD₄, respectively), were re-suspended in 20 mM HEPES, 2mM EDTA (pH 7.4), homogenised and centrifuged at 40,000 g (20 min, 4°C.). After re-suspension, homogenization and centrifugation as above,the final pellet was re-suspended in 20 mM HEPES, 100 mM NaCl, 10 mMMgCl₂, 1 mM EDTA (pH 7.4) and aliquots were kept at −80° C.[³H]-Spiperone Binding experiments were performed in 96 deep-wellpolypropylene plates in 50 mM Tris/HCl, 120 mM NaCl, 5 mM KCl, 5 mMMgCl₂ (pH 7.4). Compounds of invention were serially diluted in DMSO at100 fold final concentrations in the assay (1% DMSO final in the assay).Displacement was performed in the presence of 0.3 nM [³H]-Spiperone. Thereaction was initiated by the addition of membrane suspension (4 μg and12 μg of protein for CHO-hD₃- and CHO-hD₄ membranes, respectively) andlasted for 90 or 100 min (for hD₃ or hD₄ membranes, respectively) at 23°C. in a final volume of 500 μl. Non specific binding (NSB) wasdetermined in the presence of 1 μM Spiperone. The binding reaction wasstopped by rapid filtration through GF/B filterplates pre-soaked in 0.5%polyetylenimmine (PEI) using a Packard cell harvester. After washingwith ice-cold 0.9% NaCl, the plate was left to dry before the additionof Microscint 20 (50l/well, PerkinElmer). Radioactivity was counted witha TopCount (PerkinElmer). Data were analysed by non-linear regressionanalysis using GraphPad Prism 5.0 (GraphPad Software). Saturationbinding experiments were performed similar to the competition bindingexperiments using a radioligand concentrations ranging from 0.015 to 4.0nM. Ref: Mackenzie R. G. et al. (1994). Characterization of the humandopamine D3 receptor expressed in transfected cell lines. Eur. J.Pharmacol., 266:79-8

[¹²⁵I]-70H-PIPAT Binding Assay at rat native D₃ receptor on membranesfrom rat ventral striatum. Homogenates from frozen rat brain ventralstriatum (nucleus accumbens and olfactory tubercles), were prepared asdescribed by Burris et al. (1994). [¹²⁵I]-70H-PIPAT binding assay at D₃receptors was performed in 50 mM Tris-HCl (pH 7.0), 50 mM NaCl, 100 μMGpp(NH)p (Guanosine 5′-[β,γ-imido]triphosphate) and 0.02% BSA, i.e.conditions which inhibit the [¹²⁵I]-7-OH-PIPAT binding to D₂ and5HT_(1A) receptors. Compounds of invention were serially diluted in DMSOat 100 fold final concentrations in the assay (1% DMSO final in theassay). Displacement experiments were performed in the presence of 0.2nM [¹²⁵I]-70H-PIPAT. The reaction, carried out in a final volume of 200μl, was initiated by the addition of membrane suspension (about 20μg/well protein) and lasted 45 min at 37° C. Non specific binding (NSB)was determined in the presence of 1 μM SB277011A. The binding reactionwas stopped by rapid filtration through GF/C filterplates pre-soaked in0.5% polyetylenimmine (PEI) using a Packard cell harvester. Afterwashing with ice-cold 50 mM Tris (pH 7.4) and addition of Microscint 20(50 l/well, PerkinElmer), radioactivity was counted with a TopcCount(PerkinElmer). Data were analyzed by non-linear regression analysisusing GraphPad Prism 5.0 (GraphPad Software). Ref: Burris, K. D.; Filtz,T. M.; Chumpradit, S.; Kung, M. P.; Foulon, C.; Hensler, J. G.; Kung, H.F.; Molinoff P. B. Characterization of[125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino]tetralinbinding to dopamine D3 receptors in rat olfactory tubercle. J.Pharmacol. Exp. Ther. 1994, 268, 935-942.

[³H]-Spiperone Binding Assay at hD₂ recombinant receptor. CHO cellsstably expressing human dopamine receptor type 2, long variant(hD_(2L)), coupled to Gα16 protein (CHO-Gα16-hD_(2L)) were re-suspendedin 20 mM HEPES, 2 mM EDTA (pH 7.4), homogenised and centrifuged at40,000 g (20 min, 4° C.). After re-suspension, homogenization andcentrifugation as above, the final pellet was re-suspended in 20 mMHEPES, 100 mM NaCl, 10 mM MgCl₂, 1 mM EDTA (pH 7.4) and aliquots werekept at −80° C. [³H]-Spiperone Binding experiments were performed in 96deep-well polypropylene plates in 50 mM Tris/HCl, 120 mM NaCl, 5 mM KCl,5 mM MgCl₂ (pH 7.4). Compounds of invention were serially diluted inDMSO at 100 fold final concentrations in the assay (1% DMSO final in theassay). Displacement was performed in the presence of 0.08 nM[³H]-Spiperone. The reaction was initiated by the addition of membranesuspension (2 μg of protein for CHO-hD₂ membranes) and lasted for 120min at 23° C. in a final volume of 1000 μl. Non specific binding (NSB)was determined in the presence of 0.1 μM Spiperone. The binding reactionwas stopped by rapid filtration through GF/B filterplates pre-soaked in0.5% polyetylenimmine (PEI) using a Packard cell harvester. Afterwashing with ice-cold 0.9% NaCl, the plate was left to dry before theaddition of Microscint 20 (50 μl/well, PerkinElmer). Radioactivity wascounted with a TopCount (PerkinElmer). Data were analysed by non-linearregression analysis using GraphPad Prism 5.0 (GraphPad Software) orXLfit Version 5.2.0.0 (Copyright © 2006-2009 ID Business Solutions Ltd).Saturation binding experiments were performed similar to the competitionbinding experiments using a radioligand concentrations ranging from0.011 to 3.0 nM. Ref: Durcan M. J. et al. (1995). Is Clozapine selectivefor the dopamine D4 receptor? Life Sciences, 57: 275-283. Petrus J. etal. (2001). Real-time analysis of dopamine: antagonist interactions atrecombinant human D2long receptor upon modulation of its activationstate. Brit. J. Pharmacol. 134, 88±97.

Functional Calcium Assay at hD₂ recombinant receptor. CHO cells stablyexpressing human dopamine receptor type 2, long variant (hD_(2L)),coupled to Gα16 protein (CHO-Gα16-hD_(2L))were seeded into black walledclear-base 384-well plates at a density of 8,000 cells per well andgrown overnight at 37° C. After washing with the assay buffer (20 mMHEPES, 145 mM NaCl, 5 mM KCl, 5.5 mM glucose, 1 mM MgCl₂ and 2 mM CaCl₂,pH 7.4) containing 2.5 mM Probenecid, cells were incubated with thecytoplasmic Ca²⁺ probe Fluo-4 AM at 1 μM (final concentration), 37° C.for 60 min. Plates were washed three times as above and placed into aFluorometric Imaging Plate Reader (FLIPR Tetra, Molecular Devices) tomonitor cell fluorescence (ex=470-495 nm, em=515-575 nm) before andafter the addition of different concentrations of test compounds.Compounds of invention were dissolved in DMSO and 200-fold diluted withassay buffer plus 0.01% Pluronic F-127. Cells were exposed first to testcompounds for 10 min, then to a submaximal concentration of the hD₂receptor agonist dopamine (EC₅₀, 50-140 nM). The fluorescence beforecompound addition (baseline) and before and after addition of agonistchallenge was monitored. The peak of Ca²⁺ stimulation (baselinesubtracted) was plotted versus the concentration of test compound andthe curve fitted using a four-parameter logistic equation (XLfit) toassess the agonist/antagonist potency and maximal response.

Preparation 290:(1R,3S)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane

(1R, 3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p15,Enantiomer 1, 25 mg, 0.1 mmol) in dichloromethane (3 mL) was stirred at0° C.; triethylamine (0.022 mL, 0.15 mmol) was added, followed by4-methylbenzenesulfonyl chloride (21 mg, 0.11 mmol) and then the mixturewas slowly warmed to room temperature and stirred at the sametemperature for 1 h. DCM was added, washed with water and brine, thendried with Na₂SO₄, filtered and concentrated. The residue waschromatographed by FC on silica gel (eluent from cHex to 40% Ethylacetate) affording(1R,3S)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p290, 33 mg, y=83%) as white solid.

The latter was suspended in 0.3 mL of EtOH and then heated untildissolution. After slow cooling to RT, crystallization was observed.Crystals were filtered and used for the molecular and crystal structuredetermination by single crystal high-resolution X-ray diffraction todetermine the absolute stereochemistry.

The X-ray data collection was performed on a plate-like crystal ofapproximate dimensions 0.26×0.22×0.02 mm mounted on a glass capillary.The X-ray intensities were measures on a Bruker Smart system equippedwith an APEXII CCD area detector.

The structure was solved by direct methods using the program Sir2011,and was refined with the program SHELXL-2014. Crystal data are reportedbelow:

Empirical formula C₈₀H₈₀F₁₂N₄O₈S₄ Formula weight 1581.72 Temperature/K293 Crystal system Orthorhombic Space group P2₁2₁2₁ a/Å 11.75(5) b/Å17.30(7)) c/Å 41.04(9) α/° 90 β/° 90 γ/° 90 Volume/Å³ 8342(52) Z, Z′ 16,4 ρ_(calc)g/cm³ 1.259 μ/mm⁻¹ 0.194 F(000) 3296 Crystal size/mm³ 0.26 ×0.22 × 0.02 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/°2.540 to 34.540 Index ranges −9 ≤ h ≤ 9, −14 ≤ k ≤ 12, −33 ≤ l ≤ 28Reflections collected 17849 Independent reflections 4938 [R_(int) =0.1815, R_(sigma) = 0.1678] Data/restraints/parameters 4938/74/686Goodness-of-fit on F² 1.003 Final R indexes [I >= 2σ (I)] R₁ = 0.0786,wR₂ = 0.1598 Final R indexes [all data] R₁ = 0.1766, wR₂ = 0.2100Largest diff. peak/hole/e Å⁻³ 0.20/−0.20 Flack parameter 0.1(2)

The compound crystallizes in the chiral orthorhombic space groupP2₁2₁2₁. The asymmetric unit comprises four molecules. The Flackparameter for the present structure is 0.094(322) by classical fit toall intensities and 0.064(210) from 639 selected quotients (Parson'smethod) strongly supporting the present absolute structuredetermination.

According to the absolute structure determination, the configuration is1R, 3S. MS (m/z): 396.4 [MH]⁺.

Preparation 291:(1S,3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane

(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,p14, 3 g) was submitted to chiral Prep HPLC (SFC) to separateenantiomers:

Preparative Chromatography:

Column Chiralpak AD-H (25 × 2.1 cm), 5μ Modifier (Ethanol + 0.1%isopropylamine) 7% Flow rate (ml/min) 45 ml/min Pressure (bar) 120Temperature (° C.) 38 DAD detection 220 nm Loop 900 μL Injection 53.3mg/injection

affording: (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(1.1 g), Enantiomer 1: Ret. Time 7.9 min, 100% ee and(1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (840 mg),Enantiomer 2: Ret. Time 10.2 min, 100% ee. (1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 2,840 mg, 3.48 mmol) in dichloromethane (15 mL) was stirred at 0° C.;triethylamine (0.73 mL, 5.22 mmol) was added, followed by4-methylbenzenesulfonyl chloride (730 mg, 3.83 mmol) and then thereaction mixture was slowly warmed to room temperature and stirred atthat temperature for 2 hrs. DCM was added, washed with water and brine,then dried with Na₂SO₄, filtered and concentrated. The residue waschromatographed by FC on silica gel (eluent from cHex to 40% Ethylacetate) affording(1S,3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane(p291, 1.1 g, y=80%) as white solid.

100 mg of(1S,3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptanewere suspended in 1 mL of EtOH and then heated until dissolution. Afterslow cooling to RT, the solution was left standing at RT for 3 daysafter which time crystallization was observed. Crystals were filteredand used for the molecular and crystal structure determination by singlecrystal high-resolution X-ray diffraction to determine the absolutestereochemistry.

The X-ray data collection was performed on a plate-like crystal ofapproximate dimensions 0.31×0.24×0.07 mm mounted on a glass capillary.The X-ray intensities were measures on a Bruker Smart system equippedwith an APEXII CCD area detector.

The structure was solved by direct methods using the program Sir2011,and was refined with the program SHELXL-2014. Crystal data are reportedbelow.

Empirical formula C₈₀H₈₀F₁₂N₄O₈S₄ Formula weight 1581.72 Temperature/K293 Crystal system Orthorhombic Space group P2₁2₁2₁ a/Å 11.567(7) b/Å17.155(9) c/Å 40.16(2) α/° 90 β/° 90 γ/° 90 Volume/Å³ 7970(8) Z, Z′ 16,4 ρ_(calc)g/cm³ 1.318 μ/mm⁻¹ 0.203 F(000) 760.0 Crystal size/mm³ 0.31 ×0.24 × 0.07 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/°1.291 to 38.640 Index ranges −10 ≤ h ≤ 10, −15 ≤ k ≤ 15, −37 ≤ l ≤ 37Reflections collected 47185 Independent reflections 6706 [R_(int) =0.0941, R_(sigma) = 0.0494] Data/restraints/parameters 6706/56/926Goodness-of-fit on F² 1.013 Final R indexes [I >= 2σ (I)] R₁ = 0.0623,wR₂ = 0.1419 Final R indexes [all data] R₁ = 0.0993, wR₂ = 0.1665Largest diff. peak/hole/e Å⁻³ 0.26/−0.24 Flack parameter −0.01(6)

The compound crystallizes in the chiral orthorhombic space groupP2₁2₁2₁. The asymmetric unit comprises four molecules. The Flackparameter for the present structure is 0.000(199) by classical fit toall intensities and −0.005(57) from 1566 selected quotients (Parson'smethod) strongly supporting the present absolute structuredetermination. According to the absolute structure determination, theconfiguration is 1S, 3R. MS (m/z): 396.4 [MH]⁺.

The compounds of the invention listed above have pKi values within therange of 7.0-10.5 at the dopamine D3 receptor. pKi results are onlyestimated to be accurate to about ±0.3-0.5.

The compounds of the invention listed above have selectivity over D2preferably greater than 10 fold.

The following Table reports the values of some of the Examples:

EX D₃ pKi D₂ fpKi D₂ pKi 2 7.11 7.02 3 7.65 6.88 5 7.02 6.28 7 7.34 5.879 8.40 6.41 10 7.91 6.73 11 8.78 6.46 12 9.2 7.13 6.67 14 7.6 5.75 157.55 5.38 16 7.38 5.84 17 7.75 5.84 19 8.26 6.17 6.10 20 8.13 6.14 218.03 6.42 24 8.48 6.79 25 8.21 6.1 26 8.98 7.15 29 7.13 <5 30 9.38 7.596.65 31 7.6 5.96 34 7.46 6.02 35 7.7 5.85 36 8.7 7.02 39 9.09 7.18 6.6240 7.6 5.82 43 7.38 5.94 44 7.54 5.89 45 8.49 6.93 48 9.04 7.24 6.62 498.82 6.91 52 7.05 6.03 53 9.26 7.20 54 7.58 5.80 55 7.05 5.42 56 8.175.89 57 8.98 6.78 58 7.12 5.66 59 9.38 7.18 60 9.01 7.21 61 7.49 5.63 628.04 nt nt 65 8.15 5.93 66 8.11 <5 67 8.59 5.89 70 8.78 6.16 6.09 718.03 <5 74 8.04 5.9 75 7.87 <5 76 8.80 6.15 79 9.02 6.44 80 7.65 <5 837.93 <5 84 7.19 <5 85 8.40 6.08 88 8.49 6.27 89 9.08 nt nt 92 9.11 6.3893 9.06 6.89 94 9.73 nt nt 97 9.56 6.91 98 7.5 nt nt 99 8.05 5.65 1008.13 5.93 101 8.31 5.99 102 8.35 6.00 104 8.00 5.80 106 8.50 6.05 1077.18 5.56 108 7.56 6.72 109 8.17 6.14 112 8.56 6.08 114 7.75 5.79 1158.72 7.01 118 9.07 7.38 6.60 119 8.06 5.73 120 7.94 5.77 121 8.07 5.92122 8.59 6.34 123 7.77 6.00 124 7.26 5.32 125 7.51 5.48 126 7.69 5.94127 8.28 6.19 6.12 128 8.64 6.47 129 8.50 6.35 130 8.18 6.16 131 8.016.16 132 8.23 6.87 133 8.76 6.06 134 8.32 5.84 135 8.09 6.54 137 8.235.70 139 8.40 5.83 140 8.11 6.20 141 9.10 6.97 6.28 142 7.69 5.87 1438.74 6.21 6.05 146 8.81 6.07 147 8.55 6.02 150 7.55 5.46 151 8.95 6.19152 8.39 5.90 155 7.08 4.96 156 8.91 6.18 157 8.22 5.77 160 8.73 6.18161 7.51 5.48 162 8.08 6.06 163 9.02 6.87 6.21 164 8.20 6.23 165 8.485.77 166 8.57 5.73 168 8.28 6.44 169 8.80 6.01 170 8.69 5.85 172 8.465.92 173 8.42 5.75 174 8.15 6.02 175 8.56 6.15 176 8.59 5.95 177 8.846.10 178 8.84 6.10 179 8.85 6.10 180 8.58 5.96 181 8.55 5.77 182 9.145.83 184 9.47 6.26 185 9.38 5.91 186 7.89 5.31 187 8.90 5.96 188 7.445.03 189 9.47 6.36 190 9.55 6.56 191 9.14 6.29 192 8.30 6.36 193 8.486.36 195 8.29 5.84 197 7.65 5.66 199 7.77 5.81 200 7.45 <5 201 8.40 5.88204 8.52 5.99 205 7.01 5.75 206 7.78 5.86 207 8.29 6.54 210 8.25 6.28211 8.15 6.97 212 8.99 6.93 213 8.98 7.09 6.53 214 7.97 6.03 215 8.386.07 216 8.10 6.01 217 8.90 6.62 220 9.24 6.92 6.32 221 9.08 7.06 6.37222 8.31 5.91 223 8.72 6.00 224 8.70 5.85 227 9.07 6.24 228 9.45 6.33229 7.28 5.63 230 7.81 6.17 231 8.57 6.68 234 8.82 7.01 6.42 235 7.825.91 236 8.44 6.12 5.79 239 8.62 6.04 240 7.99 6.33 241 8.86 6.74 6.37244 9.01 6.60 245 7.96 6.12 246 8.62 6.68 6.27 249 8.86 6.57 250 8.766.07 253 9.20 6.10 254 8.84 6.32 255 8.76 6.30 256 9.22 6.48 257 9.246.46 258 9.38 6.26 259 8.27 6.95 260 8.55 6.89 261 8.65 6.40 262 9.126.18 263 9.26 6.23 265 8.86 6.23 267 7.78 5.38 268 8.42 5.80 269 8.596.00 270 8.56 6.04 271 8.63 5.91 272 9.63 7.02 273 9.11 5.50 274 9.796.52 275 9.93 6.32 276 9.44 6.78 278 10.2 6.41 279 9.74 6.30 281 9.806.45 283 9.58 6.46 284 9.61 6.46 285 9.50 6.66 286 9.28 6.33 287 9.076.33 289 9.33 6.26 290 7.82 7.40 291 7.70 5.96 295 8.54 6.06 296 7.55 <5299 7.47 <5 300 7.35 <5 301 7.73 5.84 302 8.19 5.94 303 7.48 <5 304 7.44<5 305 7.86 <5 309 7.52 5.95 310 8.32 7.72 312 8.40 8.26 313 7.3 <5 3147.14 <5 318 7.34 <5 321 7.62 5.65

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. (canceled)
 2. A pharmaceutical composition comprising from about 0.1mg to about 500 mg of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier;wherein the compound of Formula (I) is:

wherein: A is a saturated 3-6 membered carbocyclic ring, optionallysubstituted by one or more C₁₋₄alkyl; B is a saturated 4-6 memberedheterocyclic ring, in which one or two carbon atoms are optionallyreplaced by a heteroatom selected from nitrogen and oxygen, and whereinthe ring is optionally substituted by one or more C₁₋₄alkyl; G is arylor a 5-6 membered heteroaromatic group or 8-11 membered heteroaromaticgroup, which is optionally benzofused or optionally substituted by 1, 2,3, 4, or 5 substituents selected from the group consisting of: halogen,cyano, hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkyl, haloC₁₋₄alkoxy, SF₅, C(═O)NH₂, and C(═O)(O)_(z)R₃; W isS, SO₂, O, CHR₂, or NR₃; n is 0 or 1; m is 1 or 2; p is 1 or 2; z iseach independently 0 or 1; R is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkyl; eachR₁ is independently hydrogen, OH, C₁₋₄alkoxy, F, or C₁₋₄alkyl; each R₂is independently hydrogen, OH, C₁₋₄alkoxy, F, or C₁₋₄alkyl; each R₃ isindependently hydrogen or C₁₋₄alkyl; each R₄ is independently hydrogen,C₁₋₄alkyl, —C(═O)C₁₋₄alkyl, —C(═O)C₁₋₄alkoxyC₁₋₄alkyl, or—C(═O)C₃₋₆cycloalkyl; each R₅ is independently hydrogen or C₁₋₄alkyl;each R₆ is independently hydrogen or C₁₋₄alkyl; each R₇ is eachindependently halogen, C₁₋₄alkyl, OH, or C₁₋₄alkoxy; G₁ is a phenyl or a5-6-membered heteroaromatic group or a 8-11 membered heteroaromaticgroup; any of which groups is optionally substituted by 1, 2, 3, or 4substituents selected from the group consisting of halogen, cyano,hydroxyl, amino, C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, C₁₋₄alkoxy, SF₅, C(═O)NH₂, and C(═O)(O)_(z)R₃; Y isphenyl or a moiety selected from the group consisting of a 5-6 memberedheteroaromatic group, an 8-11 membered heteroaromatic group, a saturatedmono 3-7 membered carbocyclic group and a 8-11 membered bicycliccarbocyclic group; and for any of such groups one or more ring carbonsis optionally replaced by N(R₄)_(z), O, or S; and any of which groups isoptionally substituted by 1, 2, or 3 substituents selected from thegroup consisting of halogen, cyano, hydroxyl, C₁₋₄alkylamino, C₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, oxo, —NHC(═O)C₁₋₄alkyl,—NR₅R₆, SF₅, —(CH₂)_(z)C(═O)NR₅R₆, —C(═O)(O)_(z)R₃, —C₁₋₄alkylCN,—SO₂NR₅R₆, Y′, and OY′; Y′ is phenyl or a 5-6-membered heteroaromaticgroup optionally substituted by one or two R₇ groups; provided that Y,Y′ and G₁ are not simultaneously phenyl.
 3. The pharmaceuticalcomposition of claim 2, wherein: A and B are

G is aryl, and is optionally substituted by 1 or 2 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, amino,C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,SF₅, C(═O)NH₂, and C(═O)(O)_(z)R₃; W is S, SO₂, O, CHR₂, or NR₃; n is 0or 1; m is 1 or 2; p is 1 or 2; each z is independently 0 or 1; R ishydrogen, C₁₋₄alkoxy, or C₁₋₄alkyl; each R₁ is independently hydrogen,OH, C₁₋₄alkoxy, or C₁₋₄alkyl; each R₂ is independently hydrogen, OH,C₁₋₄alkoxy, or C₁₋₄alkyl; each R₃ is independently hydrogen orC₁₋₄alkyl; each R₅ is independently hydrogen or C₁₋₄alkyl; each R₆ isindependently hydrogen or C₁₋₄alkyl; G₁ is a 5-6-membered heteroaromaticgroup, and is optionally substituted by 1, 2, or 3 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, amino,C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxy,SF₅, C(═O)NH₂, and C(═O)(O)_(z)R₃; Y is a 5-6 membered heteroaromaticgroup, and is optionally substituted by 1, 2, or 3 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, C₁₋₄alkylamino,C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, oxo,—NHC(═O)C₁₋₄alkyl, —NR₅R₆, SF₅, —(CH₂)_(z)C(═O)NR₅R₆, —C(═O)(O)_(z)R₃,—C₁₋₄alkylCN, and —SO₂NR₅R₆.
 4. The composition of claim 3, wherein: Aand B are

G is aryl, and is optionally substituted by 1 or 2 substituents selectedfrom the group consisting of halogen, hydroxyl, amino, C₁₋₄alkylamino,C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, and C(═O)NH₂; W isS; n is 0 or 1; m is 1 or 2; p is 1 or 2; each z is independently 0 or1; R is hydrogen, C₁₋₄alkoxy, or C₁₋₄alkyl; each R₁ is independentlyhydrogen, OH, C₁₋₄alkoxy, or C₁₋₄alkyl; each R₂ is independentlyhydrogen, OH, C₁₋₄alkoxy, or C₁₋₄alkyl; each R₅ is independentlyhydrogen or C₁₋₄alkyl; each R₆ is independently hydrogen or C₁₋₄alkyl;G₁ is a 5-6-membered heteroaromatic group, and is optionally substitutedby 1 substituent selected from the group consisting of halogen,hydroxyl, C₁₋₄alkylamino, C₁₋₄alkyl, haloC₁₋₄alkyl, haloC₁₋₄alkoxy,C₁₋₄alkoxy, C(═O)NH₂; Y is a 5-6 membered heteroaromatic group, and isoptionally substituted by 1 substituent selected from the groupconsisting of halogen, hydroxyl, C₁₋₄alkylamino, C₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkyl, haloC₁₋₄alkoxy, and —(CH₂)_(z)C(═O)NR₅R₆.
 5. Thecomposition of claim 2, wherein the compound of Formula (I) is:


6. The composition of claim 2, wherein the compound of Formula (I) is:


7. The composition of claim 2, wherein the compound of Formula (I) is:


8. The composition of claim 2, wherein the compound of Formula (I) is:


9. The composition of claim 2, wherein the compound of Formula (I) is:


10. The composition of claim 2, wherein the composition is an orallyadministrable composition comprising from about 10 mg to about 400 mg ofthe compound of Formula (I) or the pharmaceutically acceptable saltthereof, calculated as the free base.
 11. The composition of claim 10,wherein the composition is an orally administrable compositioncomprising from about 10 mg to about 250 mg of the compound of Formula(I) or the pharmaceutically acceptable salt thereof, calculated as thefree base.
 12. The composition of claim 2, wherein the composition is anorally administrable composition selected from the group consisting of asyrup, a suspension, an emulsion, a solution, a tablet, a capsule, and alozenge.
 13. The composition of claim 12, wherein the composition is atablet or a capsule.
 14. The composition of claim 2, wherein thecomposition is a parenterally administrable composition comprising fromabout 0.1 mg to about 100 mg of the compound of Formula (I) or thepharmaceutically acceptable salt thereof, calculated as the free base.15. The composition of claim 14, wherein the composition is aparenterally administrable composition comprising from about 1 mg toabout 50 mg of the compound of Formula (I) or the pharmaceuticallyacceptable salt thereof, calculated as the free base.
 16. Thecomposition of claim 15, wherein the composition is a parenterallyadministrable composition comprising from about 1 mg to about 25 mg ofthe compound of Formula (I) or the pharmaceutically acceptable saltthereof, calculated as the free base.
 17. The composition of claim 2,wherein the composition is a parenterally administrable compositionselected from the group consisting of an intravenous composition, asubcutaneous composition, or an intramuscular composition.
 18. Thecomposition of claim 2, wherein the composition is a buccal compositionor a sublingual composition.
 19. The composition of claim 2, wherein thecomposition is a nasally administrable composition selected from thegroup consisting of an aerosol, a drop, a gel, or a powder.
 20. Apharmaceutical composition comprising from about 0.1 mg to about 500 mgof a compound or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier; wherein the compound is selectedfrom the group consisting of:


21. A method for treating a disease in a patient in need thereof, themethod comprising administering the pharmaceutical composition of claim2 to the patient; wherein the disease is opioid use disorder, apsychotic disorder, Parkinson's disease, neuroleptic-inducedparkinsonism, tardive dyskinesia, depression, anxiety, a cognitiveimpairment, Alzheimer's disease, an eating disorder, a sexualdysfunction, a sleep disorder, emesis, a movement disorder,obsessive-compulsive disorder, amnesia, aggression, autism, vertigo,dementia, a circadian rhythm disorder, a gastric motility disorder, or agambling disorder.